Brown started in the season-opening 28–21 loss to the New England Patriots and caught nine passes for 133 yards and a touchdown. The following week, he had nine receptions for 195 yards and a touchdown in the 43–18 victory over the San Francisco 49ers. This brought his career total to 5,587 yards, good for 200th on the NFL’s all-time receiving yards list. He moved past Steelers’ legend Lynn Swann on the all-time list as well. On November 8, Brown caught a career-high 17 passes for a career-high 284 yards in a narrow 38–35 victory over the Oakland Raiders in Week 9. His 284 receiving yards broke Keenan McCardell’s mark of 232 for the Jacksonville Jaguars in 1996 for most receiving yards in a game without a receiving touchdown. On December 6, he caught eight passes for 118 yards and two touchdowns in a 45–10 victory over the Indianapolis Colts in Week 13. This game is particularly notable for a play in which Brown returned a punt for a touchdown and proceeded to leap onto the goalpost. He was flagged on the play for excessive celebration. On December 9, Brown was fined $11,576 by the NFL for the incident. For his efforts against the Colts, he earned his third career AFC Special Teams Player of the Week Award. In a 34–27 victory over the Denver Broncos, he caught 16 passes for 189 yards and two touchdowns in Week 15. For his performance against the Broncos, he was named as the AFC Offensive Player of the Week. On January 3, Brown totaled 13 receptions for 187 yards and a touchdown in a 28-12 win over the Cleveland Browns in the regular season finale.

On December 22, in Week 16, Brown broke Yancey Thigpen’s single-season team record of 1,398 receiving yards set in 1997. Brown became the second player in franchise history to amass at least 100 receptions in a season, joining former teammate Hines Ward. On December 29, he, along with Pierre Garçon of the Washington Redskins, tied Jimmy Smith as the only players to record at least five receptions in every game of an NFL season. In addition, Brown became the only receiver in NFL history to record five receptions and at least 50 yards in every game of an NFL season.

On January 8, Brown caught five passes for 124 yards and two touchdowns in a 30–12 victory over the Miami Dolphins in the AFC Wild Card Round game. His two touchdowns of 50 and 62 yards were the first time that a player had caught two 50+ yard touchdowns in a single post-season game since Randy Moss in 2001, the first time ever in the first quarter, and the first time a Steeler had two receiving touchdowns in a Wild Card game. In the Divisional Round, Brown caught six passes for 108 yards in an 18–16 road victory over the Chiefs, becoming the third Steeler with four or more 100-yard receiving playoff games. After the game, Brown broadcast the team’s locker room celebration on Facebook Live in violation of NFL rules and despite the requests of teammates Ben Roethlisberger and Ramon Foster to “keep a low profile on social media”. The broadcast included head coach Mike Tomlin speaking crudely about championship round opponent New England, for which Tomlin later apologized and disciplined Brown. Brown had been paid $244,000 by Facebook before the season to “create content” for live channels. In the AFC Championship against the Patriots, Brown had seven receptions for 77 yards in the 36–17 road loss. For his accomplishments in the 2017 season, he was ranked fourth on the NFL Top 100 Players of 2017.

Brown is the son of retired Arena Football League star Eddie Brown, who was named the best player in the league’s history in 2006. He played wide receiver for the Albany Firebirds and collegiate football for Louisiana Tech.

Brown began attending Central Michigan in 2007 after wide receivers coach Zach Azzanni told him he could fly to Michigan and try out for the team as a walk-on wide receiver. Transitioning from the quarterback position in high school to wide receiver in college was not that difficult for him, and after a few weeks, Central Michigan coaches offered him a scholarship. Brown had difficulty adjusting to the college lifestyle, and being on time for meetings and practice. Azzanni and his wife helped him get situated and into an established routine, and he soon became like a part of their family. He made his collegiate debut against Kansas on September 1. He had four receptions for 23 receiving yards in the 52–7 loss. In the next week’s game against Toledo, he had nine receptions for 105 receiving yards and his first collegiate touchdown, a six-yard pass from Dan LeFevour, in the 52–31 victory. On October 6, against Ball State, he had six receptions for 43 receiving yards and a receiving touchdown to go along with a nine-yard rushing touchdown in the 58–38 victory. On November 23, against Akron, he had 15 receptions for 174 yards in the 35–32 victory. The Chippewas finished with an 8–5 record, won the MAC, and qualified for a bowl game. In the 2007 Motor City Bowl against Purdue, he had four receptions for 94 receiving yards and a receiving touchdown in the 51–48 loss. During his first season at Central Michigan, Brown played in 14 games. He played well enough to win the Mid-American Conference Freshman of the Year and was All-Conference as a returner. For his freshman season, he had 102 receptions for 1,003 yards and six touchdowns. His 102 receptions led the Mid-American Conference in 2007.

Brown started every game during his sophomore season in 2008. In the third game of the season, against Ohio, he had 10 receptions for 78 receiving yards to go along with a 75-yard punt return for a touchdown in the 31–28 victory. On October 11, against Temple, he had three receptions for 33 yards and a season-high two touchdown receptions. The next week, against Western Michigan, he had 10 receptions for 113 yards and threw a two-yard touchdown pass in the third quarter of the 38–28 victory. On November 1, against Indiana, he had seven receptions for 138 receiving yards and two receiving touchdowns in the 37–34 victory. On November 28, while playing at Eastern Michigan, he had seven receptions for a season-high 172 yards and a touchdown. The Chippewas finished with an 8–4 record and qualified for the 2008 Motor City Bowl. In the bowl game against FAU, he had 11 receptions for 92 receiving yards in the 24–21 loss. For the season, Brown hauled in 93 receptions for 998 yards and seven touchdowns. His 410 punt return yards and 791 kick return yards that season led the conference.

After a slow start to the season in a 19–6 loss against Arizona, Brown had ten receptions for 71 receiving yards and a receiving touchdown against Michigan State. In addition, he completed a 24-yard pass and recorded 150 net kickoff return yards in the 29–27 victory over the Spartans. In the season’s third game against Alcorn State, he had a 55-yard punt return for a touchdown in the first quarter of the 48–0 victory. Against Akron on September 26, 2009, Brown had nine receptions for 89 receiving yards and a season-high two receiving touchdowns in the 48–21 victory. On October 3, against Buffalo, he had six receptions for 112 receiving yards and a receiving touchdown in the 20–13 victory. In the next game, against Eastern Michigan, he had four receptions for 110 receiving yards and one receiving touchdown in the 56–8 victory. Over the next two games, both victories over Western Michigan and Bowling Green, he recorded his fourth and fifth consecutive game with a receiving touchdown. On November 11, he had 13 receptions for 129 receiving yards and one receiving touchdown in the 56–28 victory over Toledo. In the following game against Ball State, he had 11 receptions for 170 receiving yards and a receiving touchdown in the 35–3 victory. In the MAC Championship against Ohio, he had eight receptions for 66 receiving yards in the 20–10 victory.

In his last collegiate game on January 6, 2010, against Troy in the GMAC Bowl, Brown had a season-high 13 receptions for 178 yards in the 44–41 victory. He finished 2009 with single-season bests of 110 receptions (also a school record), 1,198 receiving yards, and nine touchdowns. Brown contributed to a historic season for Central Michigan. The team set a school record for wins with 12. For his career at Central Michigan, he had a school-record 305 receptions, (including the top three seasons with the most receptions in school history), 3,199 receiving yards (fourth all-time), and 22 touchdowns (third all-time). On January 7, 2010, he announced he would forgo his senior season and enter the 2010 NFL Draft.

Using a pick received in a trade with the Arizona Cardinals, the Pittsburgh Steelers selected him in the sixth round with the 195th overall pick in the 2010 NFL Draft. He was the 22nd of 27 wide receivers selected in the draft, and the second by the Pittsburgh Steelers behind Emmanuel Sanders. He picked the jersey number 84, which he explained: “Eight times four is 32. Thirty-two teams looked past me, even the Steelers. So every time I go out there it’s a little added motivation.”

On June 15, 2010, the Pittsburgh Steelers signed Brown to a three-year, $1.28 million contract with a signing bonus of $73,075.

On September 19, 2010, Brown made his NFL debut against the Tennessee Titans and returned two kickoffs and a punt for 128 yards, including an 89-yard touchdown from a reverse on the first play of the game, in the 19–11 victory. He became the first player since Steve Smith Sr. for the Carolina Panthers in 2001 to record a kickoff return touchdown in his first career game. On October 3, Brown made his first NFL catch for a six-yard gain during a 17–14 loss to the Baltimore Ravens in Week 4. During the regular-season finale against the Cleveland Browns, Brown made a season-high four catches for 52 yards in a 41–9 victory. He finished his rookie season with 16 receptions for 167 yards in ten games.

The Steelers finished the 2010 season atop the AFC North and earned the #2-seed with a 12–4 record. On January 15, 2011, Brown appeared in his first postseason game and caught a 58-yard pass from Ben Roethlisberger to set up the game-winning touchdown. He finished his first playoff game with a season-high 75 yards on three receptions as the Steelers defeated the Ravens in the AFC Divisional Round by a score of 31–24. The following week in the AFC Championship against the New York Jets, at the two-minute warning, Brown caught a 14-yard pass on 3rd & 6, sealing the 24–19 victory for the Steelers and advancing them to Super Bowl XLV. In his first Super Bowl, Brown handled four kickoff returns, four punt returns, and finished with one catch for one yard in the 31–25 loss to the Green Bay Packers.

The Steelers finished 12–4 and received a playoff berth. On January 8, 2012, Brown caught five passes for 70 yards and had one carry for 18 yards in a 29–23 overtime loss to the Denver Broncos in the AFC Wild Card Round.

On July 28, 2012, the Steelers signed Brown to a five-year, $42.5 million extension that included an $8.5 million signing bonus.

Brown finished the 2013 season with 110 receptions for 1,499 yards and eight touchdowns. On December 27, 2013, Brown was selected for the Pro Bowl as a receiver and a punt returner. On January 3, 2014, Brown was named to the AP All-Pro team for the first time in his career. He was ranked 23rd by his fellow players on the NFL Top 100 Players of 2014.

In 2014, Brown led the NFL in receptions (129), receiving yards (1,698), and was tied for second in touchdowns (13); all three were new team records. He became the first Steeler to lead the league in receiving yards since Roy Jefferson in 1968. The Steelers made the playoffs and faced off against the Ravens in the Wild Card Round. In the 30–17 loss, he had nine receptions for 117 yards. His successful season garnered him a third Pro Bowl selection. He was ranked eighth by his fellow players on the NFL Top 100 Players of 2015.

In the 2016 season, Brown posted his fourth consecutive and fifth career season with at least 1,000 receiving yards, earning him his fourth consecutive and fifth career Pro Bowl selection on December 20, 2016. He was named First Team All-Pro for the third consecutive time.

On March 8, 2016, Brown was announced as one of the celebrities who competed on season 22 of Dancing with the Stars. He was paired with professional dancer Sharna Burgess. Brown and Burgess were eliminated during the semifinals of the show and finished the competition in fourth place overall.

On February 27, 2017, Brown signed a new five-year contract with the Steelers through the 2021 season. The contract was a four-year extension worth $68 million ($19 million guaranteed at signing) with a $17 million annual salary, making Brown the highest paid wide receiver in the NFL.

With the retirement of Hines Ward during the offseason, Brown entered training camp competing with Mike Wallace and Emmanuel Sanders to be the starting wide receivers. Brown and Wallace were subsequently named the starters at the position to begin the regular season. In December 2018, former Steelers safety Ryan Clark claimed that during a practice in 2012, Brown started shouting at defensive coordinator Dick LeBeau and began yelling at players on the defense, saying, “Don’t touch me. I’m the franchise.”

Brown is the father of four sons and a daughter. He has three sons with Chelsie Kyriss and two other children by two other women. In 2018, he was featured in recording artist Drake’s music video for “God’s Plan”. On July 18, 2018, Brown was announced as the cover athlete for Madden NFL 19. In September 2019, Brown re-enrolled for online classes at his alma mater, Central Michigan University.

On March 9, 2019, the Steelers agreed to trade Brown to the Oakland Raiders in exchange for a third and a fifth-round selection in the 2019 NFL Draft. The deal became official on March 13, 2019. Prior to the trade to Oakland, reports surfaced that the Steelers were “close to a deal” with the Buffalo Bills, but that the deal was cancelled after Brown protested on social media.

On September 7, 2019, the same day he was released by the Raiders, Brown agreed to a one-year contract with the New England Patriots worth up to $15 million, with a $9 million signing bonus. Additionally, on September 9, the Patriots added a second-year option in Brown’s contract in which he would receive $20 million if picked up. Brown wore #17 with the Patriots as his #84 was taken by Benjamin Watson.

Brown posted on Twitter that he was retiring from the NFL on September 22, 2019, but changed his mind four days later. On July 20, 2020, he implied he was retiring again, but again expressed interest in playing a few days later.

Brown is also the cousin of Baltimore Ravens wide receiver Marquise Brown, who was drafted in 2019.

On September 10, 2019, Brown’s former trainer filed a lawsuit alleging he sexually assaulted her on three occasions. She claimed that he exposed himself to her, ejaculated on her back, and raped her. Brown and his legal team denied the allegations. On September 16, a second woman accused him of sexual misconduct. A Pittsburgh-based doctor, who Brown worked with while with the Steelers, also sued Brown for $11,500 in unpaid fees.

On January 2, 2019, Brown took part on the first season of the American version of The Masked Singer. He competed in the show wearing “The Hippo” costume and sang “My Prerogative” by Bobby Brown before being eliminated in the first episode.

On July 31, 2020, Brown was suspended for the first eight weeks of the 2020 NFL season for multiple violations of the league’s personal-conduct policy.

Brown visited the Tampa Bay Buccaneers on October 24, 2020. He signed a one-year contract with the team on October 27, which reportedly included $1 million in base salary and active game bonuses, and $1.5 million in performance incentives. Brown will wear #81 for the Buccaneers as #84 was taken by Cameron Brate while #17 was taken by Justin Watson. Brown was reinstated from suspension and the team activated him on November 3, 2020. In his first game back on Sunday Night Football in Week 9, he was targeted five times, catching three passes for 31 yards. However, the Buccaneers were routed by the New Orleans Saints 3–38.

On January 13, 2020, following several domestic incidents in which police were called to Brown’s home in Hollywood, Florida, the Hollywood Police Department stated they no longer want Brown to be associated with their youth league (PAL). The Hollywood police department returned a check from Brown and issued a trespass order preventing him from being involved with their youth league while saying in a statement, “We do not want him to continue to affect our youth, or influence them in a negative way.” Days later on January 21, it was reported that Brown and an accomplice had attacked a moving truck driver at the home. Glenn Holt, working as Brown’s trainer was arrested, while a warrant for Brown’s arrest was issued a day later with a felony charge of battery and burglary. He turned himself in a night later on January 23. Brown was officially charged with felony burglary of a vehicle, misdemeanor battery, and misdemeanor criminal mischief on March 20, 2020. On June 12, 2020, Brown pleaded no contest to the felony battery and burglary charges and received two years of probation. He was also ordered to undergo 100 hours of community service, a 13-week anger management counseling program, and a psychological evaluation.