Smith-Schuster began playing football at the age of eight. He changed his name in football program listings in 2012 from “John” to “Ju-Ju,” a nickname an aunt gave him when he was young, and legally changed his last name from “Smith” to “Smith-Schuster” while in college as a tribute to his step-father. In his youth, Smith-Schuster was coached by Snoop Dogg when he played youth football with the Snoop Youth Football League, where Snoop gave Smith-Schuster the nickname “Sportscenter,” telling the boy that he believed one day his highlights would be shown on the flagship ESPN show.

Smith-Schuster earned immediate playing time as a true freshman in 2014. In his first career game, he had four receptions for 123 yards against Fresno State. Against the Washington State Cougars, he had six receptions for 74 yards and three touchdowns. He finished the 2014 season with 54 receptions for 724 yards and five touchdowns. As a sophomore in 2015, Smith-Schuster played 14 games with a career-high 1,454 receiving yards and 10 touchdowns.

As a junior in 2016 the Trojans used Smith-Schuster less. He played in 13 games with 914 receiving yards and 10 touchdowns. That year he also helped the Trojans to a victory in the Rose Bowl over the Penn State Nittany Lions, catching seven passes for 133 yards and a receiving touchdown over the course of the game. After the 2016 season, Smith-Schuster announced on Twitter that he had decided to forgo his senior year and enter the 2017 NFL Draft, before signing with sports agency Roc Nation. Fellow USC alum Lynn Swann said of Smith-Schuster’s pro-potential based upon his college career, “He’s got the size. He’s got the strength. He’s got the attitude … In Juju, you’ve got a guy who’s got the kind of versatility you might be looking for.” Though he left before graduation, Smith-Schuster later returned to take summer courses at USC in order to work towards finishing his university degree.

The Pittsburgh Steelers selected Smith-Schuster in the second round (62nd overall) of the 2017 NFL Draft. He was the youngest player selected in the 2017 Draft and was the 13th USC wide receiver drafted in the last 15 years.

On May 17, 2017, the Steelers signed him to a four-year, $4.19 million contract with $1.84 million guaranteed and a signing bonus of $1.19 million.

During Week 7 against the Cincinnati Bengals, Smith-Schuster caught his third touchdown pass of the season, a 31-yard reception, becoming the first player in NFL history to score three touchdowns before the age of 21. On October 29, 2017, Smith-Schuster made his first career start at wide receiver and had a breakout performance with a season-high seven receptions for 193 receiving yards and scored a 97-yard touchdown during a 20–15 victory on Sunday Night Football against the Detroit Lions. The 97-yard touchdown reception was also the longest pass play in team history and the longest touchdown reception in the league during the 2017 season. Smith-Schuster started at wide receiver in place of Martavis Bryant, who was benched by head coach Mike Tomlin after publicly asking for a trade. His 193 yards was second only to Jimmy Orr’s 205 in 1958 for the most receiving yards by a Steelers rookie and the most by any NFL rookie since Mike Evans’ 209 in Week 11 of 2014. He was named AFC Offensive Player of the Week for his Week 8 performance.

On December 5, 2017, Smith-Schuster was suspended for one game after delivering a blindsided block to Cincinnati Bengals’ linebacker Vontaze Burfict in Week 13. In Week 17, he had a 96-yard kick return for a touchdown and also caught nine passes for 143 yards and a touchdown during a 28–24 victory against the Cleveland Browns. With this performance, Smith-Schuster became the youngest player in NFL history to have over 1,000 all-purpose yards. He was also named AFC Special Teams Player of the Week for his kick return touchdown. He finished the season with 58 receptions for 917 yards and seven touchdowns, with the latter two statistics leading all rookies. He was named the Polynesian Pro Football Player of the Year for 2017.

The Steelers finished first in the AFC North with a 13–3 record and earned a first-round bye. On January 14, 2018, Smith-Schuster started in his first playoff game and made three receptions for five yards and a late touchdown in a narrow 45–42 loss to the Jacksonville Jaguars in the Divisional Round.

On January 18, 2018, the Pittsburgh Steelers promoted quarterback’s coach Randy Fichtner to offensive coordinator after they opted not to renew former offensive coordinator Todd Haley’s contract. Smith-Schuster entered training camp slated as a starting wide receiver after the Steelers traded Martavis Bryant to the Oakland Raiders for a third-round pick in the 2018 NFL Draft. Tomlin named Smith-Schuster a starting wide receiver to begin the regular season, alongside Antonio Brown.

Smith-Schuster started his second NFL season strong with nine receptions for 116 receiving yards in the 21–21 tie against the Cleveland Browns. He followed that performance up with a career-high 13 receptions for 121 receiving yards and a touchdown in a 42–37 loss to the Kansas City Chiefs. In Week 3, against the Tampa Bay Buccaneers, he recorded nine receptions for 116 yards in the 30–27 victory on Monday Night Football. Smith-Schuster broke another NFL record on November 25, 2018 against the Denver Broncos when he became to the first player ever to have two offensive touchdowns of at least 97 yards. The touchdown was part of a 13-reception, 189-yard performance in the loss. In Week 14 against the Oakland Raiders, Smith-Schuster caught 8 passes for 130 yards and 2 touchdowns in a 24–21 loss. During Week 16 against the New Orleans Saints, Smith-Schuster finished with 115 receiving yards as the Steelers lost 28–31; however, as the Steelers were progressing down the field into scoring position, Smith-Schuster committed a game-ending fumble. This would ultimately be one of the causes of the Steelers missing the playoffs that season, as wins by the Baltimore Ravens and Indianapolis Colts the following week officially eliminated them.

Smith-Schuster was voted team MVP by his teammates for the 2018 season, finishing the season with a team-high 111 receptions and 1,426 yards. He also had seven touchdowns on the season, finishing second on the team only to Antonio Brown’s 15 touchdown catches. Smith-Schuster made his first career Pro Bowl in 2018 as an alternate, after teammate Antonio Brown announced that he would not participate in the game because of an injury. He received an overall grade of 81.8 from Pro Football Focus in 2018, which ranked as the 16th highest grade among all qualifying wide receivers.

Smith-Schuster has used Twitch to stream himself playing games including Fortnite and Call of Duty: WWII. In 2018 he participated in Ninja’s record-breaking Fortnite stream including Drake and Travis Scott. While injured during the 2019 season, Smith-Schuster participated in a live Thursday Night Football stream with TimTheTatman, for which he was paid $100,000.

In February 2018, Smith-Schuster announced a partnership with the popular gaming group FaZe Clan to sell merchandise. He now has a YouTube channel using his full name that posts Call of Duty, Fortnite Battle Royale, and daily life videos that often feature his French bulldog Boujee.

In October 2020 Smith-Schuster announced that he would own a new esports team called Team Diverge. The team intends to include content from other athletes and musicians and would establish its own gaming house after the 2020 NFL season ends.