Brown eventually chose to continue his college career at the University of Florida, signing a National Letter of Intent in December 2012 and enrolling in May 2013. Standing at 6-foot-8 and weighing 363 pounds, Brown was the Gators biggest offensive lineman since Max Starks, who played for the team in 2003 and is believed to be the biggest player to ever wear a Florida Gators uniform. At the beginning of his first year at Florida, Brown was used mainly on field goals and "Jumbo" packages in short yardage situations. He took over the starting tackle job in the Georgia game after Tyler Moore was injured and lost for the year. Brown moved to starting guard at the beginning of the 2014 season.
On May 2, 2015, Brown was selected by the San Francisco 49ers in the 7th round with the 244th overall pick of the 2015 NFL Draft. Brown started the last 2 regular season games of his rookie season and played in a total of 5 games. After being asked in an interview to name the blocker that gives him the most trouble, Denver Broncos' linebacker and Super Bowl MVPVon Miller said, "I feel like Trent Brown has a very bright future in the National Football League. He's 6-foot-8. He knows how to use his arms, knows how to use his wingspan and he has length. So I feel like he's young and people haven’t really seen him, but I feel like he’s one of the better tackles in the National Football League." On August 16, 2017, Miller made a similar remark about Brown to the San Francisco Chronicle after the Broncos and 49ers had a joint practice, stating,
"He's the best right tackle in the National Football League! And he may even be a top-five tackle, period, in the National Football League. There’s not another tackle who’s that tall, that big and can move the way he moves.”
Brown started all 16 regular season games for the 49ers in 2016. In 2017, Brown started 10 games at right tackle before being placed on injured reserve on December 16, 2017 with a shoulder injury.
On April 27, 2018, Brown was traded along with the 143rd selection in the 2018 NFL Draft to the New England Patriots for the 95th selection. Brown's arrival was part of Patriots head coach Bill Belichick's attempt to build one of the heaviest rosters for a power-running offense. After playing right tackle during his tenure with the 49ers, Brown became the Patriots starting left tackle in 2018, starting all 16 games. With Brown, the Patriots reached and went on to win Super Bowl LIII.
On March 13, 2019, Brown signed a four-year, $66 million contract with the Oakland Raiders with $36.75 million guaranteed, making him the highest-paid offensive lineman in the league. Head coach Jon Gruden announced that Brown would play right tackle with Kolton Miller remaining at left tackle. In his first 11 games with the Raiders, Brown allowed only one sack in 326 pass-blocking snaps. On December 17, 2019, Brown was named a Pro Bowl selection for the first time of his career. The next day, he was placed on IR, ending his season.
