The Kansas City Chiefs selected Berry in the first round (fifth overall) of the 2010 NFL Draft. He became the highest drafted defensive back since Sean Taylor in 2004, and the highest drafted Tennessee Volunteer since Jamal Lewis. Berry selected number 29 as his jersey number in honor of former Tennessee defensive back standout Inky Johnson, whose career was cut short due to an injury and also as a tribute to his hometown Fairburn, Georgia, and the main road U.S. Route 29.

Berry played cornerback and quarterback, earning a 37–5 record as a starter at Creekside. He was teammates with Rokevious Watkins and Terrance Parks. Following his stellar high school career, Berry was invited to play in the 2007 U.S. Army All-American Bowl. Berry was considered the top player in Georgia and the top cornerback prospect by every recruiting service, and Rivals.com ranked him the #3 player in the nation. He was once clocked at 4.38-4.41 range at the 40-yard dash at a soft indoor surface at a high school Combine.

Following Tennessee’s 37–14 loss to Virginia Tech in the 2009 Chick-fil-A Bowl, Berry announced his decision to forgo his final year of college football eligibility, entering the 2010 NFL Draft. He attended the NFL Scouting Combine in Indianapolis, Indiana and performed all of the combine and positional drills. Berry finished second among safeties in the 40-yard dash and fifth in the bench press. On March 16, 2010, Berry opted to participate at Tennessee’s pro day, but chose to stand on his combine numbers and only performed positional drills.

On July 30, 2010, the Kansas City Chiefs signed Berry to a six-year, $60 million contract that includes $34 million guaranteed and made him the highest paid safety in the league history.

He made his professional regular season debut and first career start in the Kansas City Chiefs’ season-opener against the San Diego Chargers and recorded his first career tackle on tight end Antonio Gates after he caught an 11-yard pass in the first quarter of their 21–14 victory. He finished his debut with six combined tackles. On October 24, 2010, Berry recorded four solo tackles, two pass deflections, forced a fumble, and made his first career interception off a pass by quarterback Todd Bouman during a 42–20 victory against the Jacksonville Jaguars. The following week, he made a season-high ten combined tackles (seven solo), deflected a pass, and intercepted a pass by Ryan Fitzpatrick in their 13–10 overtime victory over the Buffalo Bills. In Week 9, he recorded four combined tackles and a season-high two sacks on quarterback Jason Campbell in the Chiefs’ 23–20 overtime victory at the Oakland Raiders. It marked Berry’s first career sack. On December 26, 2010, Berry made four solo tackles, broke up a pass, and returned an interception for a 54-yard touchdown to mark the first score of his career. His interception was off a pass by quarterback Kerry Collins that was originally intended for Nate Washington and occurred in the second quarter of their 34–14 victory against the Tennessee Titans in Week 16. He finished his rookie season with a career-high 92 combined tackles (77 solo), nine pass deflections, four interceptions, two sacks, a touchdown, and a forced fumble in 16 games and 16 starts. He led the team in interceptions (4), and was second only to Derrick Johnson in tackles and solo tackles.

On May 4, 2010, it was reported that Berry had signed an endorsement deal with Adidas. He established the Eric Berry Foundation in 2011 that strives to provide safe environments for children to participate in team sports. His first project was a turf football field he funded in Fairburn, Georgia. He also hosts annual youth football camps in Atlanta, Tennessee, and Kansas City with proceeds going to the Eric Berry Foundation.

On January 24, 2011, it was reported that Berry would play in the 2011 Pro Bowl as a replacement for Troy Polamalu, who was appearing in the AFC Championship with the Pittsburgh Steelers. He became the first Chiefs rookie to be selected to the Pro Bowl since linebacker Derrick Thomas. Berry had a big impact on the team’s defense, helping to improve it from 29th best unit in the 2009 season in terms of points allowed to 11th in the 2010 season, In addition to starting every game, Berry was on the field for almost half of Kansas City’s special teams plays and was the only Chiefs defender to play every defensive snap.

The Kansas City Chiefs finished first in the AFC West with a 10–6 record. On January 9, 2011, Berry recorded ten combined tackles and a season-high four pass deflections during a 30–7 loss to the Baltimore Ravens in the AFC Wildcard Game.

He started the Kansas City Chiefs’ season-opener against the Buffalo Bills, but sustained a torn ACL on the Bills’ second offensive drive during the first quarter of their 41–7 loss. He sustained the injury during a seven-yard run by C. J. Spiller and went down untouched while attempting to switch direction in pursuit of him. On September 14, the Kansas City Chiefs officially placed him on injured reserve prematurely ending his second season before he recorded a stat. On September 29, 2011, he underwent surgery to repair the torn ligament. Throughout the season, Jon McGraw replaced Berry in the lineup. On December 13, 2011, the Kansas City Chiefs fired head coach Todd Haley after they stood at a 5–8 record. Defensive coordinator Romeo Crennel was named interim head coach for the last three games.

Berry returned to training camp in 2012 and reclaimed his role as the starting strong safety. Head coach Romeo Crennel named Berry and Lewis the starting safety duo to begin the regular season.

On November 1, 2012, Berry recorded eight combined tackles, a pass deflection, and intercepted a pass by Philip Rivers during a 31–13 loss at the San Diego Chargers. In Week 11, he collected a season-high 11 solo tackles in the Chiefs’ 28–6 loss to the Cincinnati Bengals. On December 16, 2012, Berry tied his season-high of 11 solo tackles and broke up a pass in their 15–0 loss at the Oakland Raiders. On December 26, 2012, Berry was announced as one of six Chiefs players to be a voted to the 2013 Pro Bowl. On December 31, 2012, the Kansas City Chiefs fired head coach Romeo Crennel after they finished with a 2–14 record. He finished the 2012 season with 86 combined tackles (73 solo), ten pass deflections, and an interception in 16 games and 16 starts.

On September 19, 2013, Berry recorded five solo tackles, two pass deflections, and returned an interception off Michael Vick for a 37-yard touchdown in the Chiefs’ 26–16 victory at the Philadelphia Eagles. In Week 12, he made a season-high eight solo tackles, broke up a pass, and a sack during a 41–28 loss to the San Diego Chargers. On December 15, 2013, Berry collected three combined tackles, two pass deflections, a season-high two interceptions, and a touchdown during a 56–31 victory at the Oakland Raiders. During the first quarter, he intercepted a pass by Matt McGloin and returned it for a 37-yard touchdown. Head coach Andy Reid decided to rest Berry for the Chiefs’ Week 17 matchup at the San Diego Chargers after the Chiefs had already clinched a playoff berth with an 11–4 record. On December 27, 2013, it was announced that Berry was one of eight players from the Chiefs to be voted to the 2014 Pro Bowl, marking his third consecutive Pro Bowl. Berry attained the second highest overall grade among safeties from Pro Football Focus in 2013.

He finished the season with 74 combined tackles (66 solo), ten pass deflections, a career-high 3.5 sacks, three interceptions, two fumble recoveries, and two touchdowns in 15 games and 15 starts. On January 4, 2014, Berry started in the AFC Wildcard Game and recorded nine combined tackles and a forced fumble during their 45–44 loss at the Indianapolis Colts. On January 26, 2014, he started in the 2014 Pro Bowl for Team Sanders and recorded two pass deflections and an interception during their 22–21 victory over Team Rice. He intercepted a pass by Drew Brees in the endzone that was intended for Larry Fitzgerald and lateraled in to Darrelle Revis after a 13-yard gain at the end of the first quarter.

Berry remained the starting strong safety during training camp and was officially named the starter by defensive coordinator Bob Sutton for the season-opener, along with free safety Husain Abdullah. He started the Kansas City Chiefs’ season-opener against the Tennessee Titans and recorded a career-high 15 combined tackles (14 solo) and a pass deflection during their 26–10 loss. On September 14, 2014, Berry sustained a high ankle sprain against the Denver Broncos and was sidelined for five consecutive games (Weeks 3–8). On November 20, 2014, Berry recorded five combined tackles and began complaining of chest pains after their 24–20 loss at the Oakland Raiders. On December 8, 2014, it was reported that a mass was discovered in Berry’s chest and he was diagnosed with Hodgkin’s lymphoma. Berry was placed on the Chiefs’ non-football illness list, ending his 2014 season. Berry’s doctor, Dr. Christopher Flowers, a lymphoma specialist at Emory University Hospital in Atlanta, said of Berry’s diagnosis, “This is a diagnosis that is very treatable and potentially curable with standard chemotherapy approaches. The goal of Mr. Berry’s treatment is to cure his lymphoma and we are beginning that treatment now.” He finished the 2014 season with 37 combined tackles (32 solo) and two pass deflections in six games and five starts.

On July 28, 2015, the Kansas City Chiefs announced that Berry had been cleared to resume football activities and was declared clear of cancer nearly nine months after his initial diagnosis. Head coach Andy Reid opted to bring Berry back gradually and named him the backup free safety behind Husain Abdullah to begin the 2015 regular season.

On September 17, 2015, he made his first start of the season and recorded four solo tackles in his return to Arrowhead Stadium as the Chiefs lost to the Denver Broncos 31–24. In Week 7, Berry recorded six combined tackles, a pass deflection, and intercepted a pass by Ben Roethlisberger in a 23–13 win against the Pittsburgh Steelers. On November 15, 2015, Berry made two solo tackles, a career-high four pass deflections, and intercepted a pass by quarterback Peyton Manning during a 29–13 victory at the Denver Broncos. The following week, he made a season-high eight solo tackles in the Chiefs’ 33–3 victory at the San Diego Chargers. On December 24, 2015, the Kansas City Chiefs announced that Berry was one of five Chiefs players to be voted to the 2016 Pro Bowl. He finished the 2015 season with 61 combined tackles (55 solo), ten pass deflections, and two interceptions in 16 games and 15 starts. Pro Football Focus gave Berry an overall grade of 87.7, which ranked fifth among all qualifying safeties in 2015. He also received the fourth highest coverage grade among safeties (85.2).

The Kansas City Chiefs finished second in the AFC West with an 11–5 record. On January 9, 2016, Berry started in the AFC Wildcard Game and recorded three combined tackles, a pass deflection, and an interception as the Chiefs routed the Houston Texans 30–0. The following game, he made seven combined tackles in Kansas City’s 27–20 loss at the New England Patriots in the AFC Divisional Round. He was named Comeback Player of the Year and was ranked 55th by his fellow players on the NFL Top 100 Players of 2016.

On March 1, 2016, the Kansas City Chiefs offered Berry a franchise tag. He decided to hold out of training camp and offseason activities in the hopes of receiving a long-term contract offer by the Chiefs. On August 28, 2016, Berry signed a one-year, $10.80 million franchise tag to remain with the Chiefs for the 2016 season after both parties were unable to come to an agreement on a long-term contract.

On November 13, 2016, Berry recorded nine combined tackles, two pass deflections, and returned an interception by Cam Newton for a 42-yard touchdown in the Chiefs’ 20–17 victory at the Carolina Panthers. In Week 13, Berry made two solo tackles, broke up a pass, returned an interception for a 37-yard touchdown, and became the first player to return an interception for a defensive two-point conversion since the rule was enacted in 2015. His two-point score occurred on an interception by quarterback Matt Ryan during the two-point conversion attempt and provided the winning score for the Chiefs’ 29–28 victory against the Atlanta Falcons. He earned AFC Defensive Player of the Week honors for his performance against the Falcons. On December 13, 2016, he collected a season-high 11 combined tackles (ten solo) during a 19–17 loss to the Tennessee Titans. On December 20, 2016, it was announced that Berry was one of four Chiefs players voted to the 2017 Pro Bowl, marking his fifth Pro Bowl selection of his career. He finished the season with 77 combined tackles (62 solo), nine pass deflections, four interceptions, a forced fumble, and two touchdowns in 16 games and 16 starts. Berry received an overall grade of 87.8 from Pro Football Focus, which ranked seventh among all safeties in 2016. He also received the fourth highest coverage grade among his position group (88.7) and fifth highest run defense grade (85.0).

On January 6, 2017, he was selected to be First-team All-Pro, marking his third All-Pro selection in his career. He was also ranked 13th by his peers on the NFL Top 100 Players of 2017 as the highest ranked defensive back.

On February 28, 2017, the Kansas City Chiefs signed Berry to a six-year, $78 million contract that includes $40 million guaranteed and a $20 million signing bonus, making him the highest-paid safety in the NFL.

He remained the starting strong safety, opposite Ron Parker, to start the regular season. He started the Kansas City Chiefs season-opener at the New England Patriots and recorded seven combined tackles, before leaving their 42–27 victory on Thursday Night Football in the fourth quarter after sustaining an apparent Achilles injury. The following day, the Chiefs announced he had ruptured his Achilles and that he would miss the rest of the season. He finished his season with seven combined tackles (four solo) in one game and one start. On September 9, 2017, the Kansas City Chiefs officially placed him on injured reserve and he underwent surgery three days later. With only one appearance, he earned an overall grade of 73.6 from Pro Football Focus.

On March 13, 2019, Eric Berry was released by the Chiefs.