During his freshman year, Fowler moved to the outside linebacker position. Fowler played in all 13 games and started his first game against Missouri. He recorded 30 tackles, including eight for loss, and 2.5 sacks. He was named to numerous freshman all-American teams. In 2013, Fowler started all 13 games for the Gators and was named a team captain for the two final games of the season. He recorded 50 tackles, including 10.5 for loss, and 3.5 sacks. In 2014, he slimmed down from 277 to 261 pounds, in an effort to be a more explosive edge player for the Gators. He recorded 60 tackles, including 15 for loss, 8.5 sacks, and two forced fumbles, and was named a first-team All-Southeastern Conference selection by the conference’s coaches. In his final game, the 2015 Birmingham Bowl vs East Carolina, he recorded three sacks helping the Gators to the 28-20 victory.

On November 19, 2014, Fowler tweeted that he would leave the school with Will Muschamp, who announced he would step down as head coach. Fowler made his intentions to forgo his remaining eligibility and enter the 2015 NFL Draft.

Fowler was selected in the first round with the third overall pick by the Jacksonville Jaguars in the 2015 NFL Draft.

On May 8, 2015, Fowler tore his ACL on the first day of mini-camp and missed the entirety of his rookie season. On May 12, four days after tearing his ACL, Fowler signed a fully guaranteed four-year, $23.5 million contract, with a $15.3 million signing bonus.

After missing his entire rookie year due to his ACL injury, Fowler made his NFL debut on September 11, 2016, in the game against the Green Bay Packers, where he made three tackles (one for a loss) as the Jaguars lost the game 27–23.

On September 10, 2017, in the 29–7 season-opening road victory over the Houston Texans, Fowler had a stellar game. He had a 53-yard fumble return for a touchdown near the end of the first half. The touchdown was the first of his NFL career. Late in the third quarter, Fowler forced a fumble off of quarterback Deshaun Watson, which was recovered by teammate Yannick Ngakoue.

On July 18, 2017, Fowler was arrested in St. Petersburg, Florida for simple battery and committing mischief. Fowler confronted a man who commented about his driving, struck the man, broke his glasses, and threw a bag containing liquor into a lake. He was released from jail the next day on a $650 bond. On March 1, 2018, Fowler pleaded no contest to battery, criminal mischief, and petty theft. He was fined $2,575, received a year of probation, and was ordered to undergo 75 hours of community service.

On May 2, 2018, the Jaguars declined the fifth-year option on Fowler’s contract. On July 20, 2018, he was suspended for one game due to violating the league’s personal conduct policy.

On October 30, 2018, Fowler was traded to the Los Angeles Rams in exchange for a compensatory third-round selection (Quincy Williams) in the 2019 NFL Draft and a fifth-round selection in the 2020 NFL Draft, which ended up being used to select Collin Johnson. Due to a change to the 3-4 defense, Fowler moved to outside linebacker with the Rams. In 8 games of 2018, Fowler finished with 21 tackles, 2 sacks, a pass defended, and a forced fumble. In the playoffs, the Rams defeated the Dallas Cowboys in the Divisional Round and Fowler recorded 2 tackles and a sack. In the NFC Championship Game against the New Orleans Saints, Fowler recorded 5 tackles and 0.5 sacks in a 26-23 overtime victory to advance to Super Bowl LIII and Fowler made a huge play in overtime when he hit Drew Brees to set up an interception by John Johnson III. The Rams played the New England Patriots in the Super Bowl but lost 13-3. Fowler recorded 4 tackles in the loss.

In December 2019, the NFLPA revealed that it had won a grievance filed on Fowler’s behalf alleging that the Jaguars had improperly fined Fowler over $700,000 for not attending rehab and medical appointments in Jacksonville during the 2018 offseason. Under the collective bargaining agreement, these appointments should have been voluntary. This incident reportedly led to the firing of Jaguars football operations chief Tom Coughlin.

On March 11, 2019, Fowler signed a one-year, $14 million contract extension with the Rams.

On March 25, 2020, Fowler signed a three-year, $48 million contract with the Atlanta Falcons.