Garrett attended Martin High School in Arlington, Texas, where he was a letterman in football, basketball, and track.

In football, he had 19.5 sacks as a senior[1] and was the 2013 recipient of the Landry Award, given to the top high school player in the Dallas-Fort Worth metroplex.

Garrett also had the third fastest 40-yard dash of all defensive linemen at the combine, which highly impressed scouts due to his size.

[35][36] At the conclusion of pre-draft process, Garrett was projected by NFL draft analyst and scouts to be the first overall player selected.

He was ranked the top overall prospect and defensive end by Sports Illustrated, ESPN, Pro Football Focus, and DraftScout.com.

[37][34][38][39] Garrett was also ranked the top edge rusher in the draft by NFL analyst Mike Mayock.

[47] Head coach Hue Jackson named Garrett and Emmanuel Ogbah the starting defensive ends to begin the regular season.

[48] On September 7, Garrett suffered a high ankle sprain during practice, causing him to miss the start of the season.

[50] Despite having four sacks in his first three games, Garrett's injury woes continued as he suffered a concussion during Week 8 against the Tennessee Titans.

[54] In week 1 against the Pittsburgh Steelers, Garrett sacked Ben Roethlisberger twice and forced two fumbles, both of which were recovered by the Browns, during the 21–21 tie game.

[57] In the 2018 season, Garrett started all 16 games and recorded 13.5 sacks, 44 combined tackles, 12 tackles-for-loss, 29 quarterback hits, three passes defensed, and three forced fumbles.

[62] During Week 2 against the Jets, Garrett finished with three sacks but also committed two roughing the passer penalties as the Browns won 23–3.

A fight ensued that resulted in Garrett, Pouncey, and Browns defensive tackle Larry Ogunjobi being ejected; Pouncey punched and kicked Garrett's head several times after the strike, while Ogunjobi pushed a helmetless Rudolph to the ground as he stood watching the fight.

Months later, before his reinstatement hearing, Garrett alleged for the first time publicly that Rudolph directed a "racial slur" at him.

[71] Garrett claimed he discussed the alleged slur immediately after the altercation with former general manager John Dorsey, head coach Freddie Kitchens, and Ogunjobi, his best friend.

(Oakland Raiders linebacker Vontaze Burfict was suspended for 12 games in 2019 due to a history of violations of player safety rules.

[77] In Week 2 against the Cincinnati Bengals, Garrett recorded a strip sack on rookie quarterback Joe Burrow which was recovered by the Browns during the 35–30 win.

[80] In Week 7 against the Cincinnati Bengals, Garrett sacked Joe Burrow two more times and forced a fumble that was recovered by the Browns during the 37–34 win.

[85] Garrett was selected for the 2020 All-Pro Team, along with three of his teammates: tackle Jack Conklin and guards Joel Bitonio and Wyatt Teller.

In a Week 14 game against the Baltimore Ravens, Garrett strip sacked Tyler Huntley, recovered the fumbled ball and returned it for his first NFL touchdown.

[97] In the 2022 season, Garrett finished with 16 sacks, 60 total tackles (37 solo), four passes defended, and two forced fumbles.

[102] All totaled, he finished the regular season with 14 sacks, earning his fifth Pro Bowl and third first-team All-Pro selections.

"[115] Garrett's half-brother, Sean Williams, was a standout basketball player for Boston College and was selected with pick number 17 in the first round of the 2007 NBA draft by the New Jersey Nets.

[117] During the 2015 offseason, Garrett decided to stop using his social media account on Twitter, citing: "There's a lot of negativity on there I don’t need in my life.

[119] On April 30, 2017, two days after the 2017 NFL draft, Garrett, along with fellow first rounders Jabrill Peppers and David Njoku, were at Progressive Field, and threw out a ceremonial first pitch.

[120][121] On September 28, 2021, a mural of Garrett (as a young child) and his grandmother Juanita was unveiled in the Playhouse Square district in downtown Cleveland.

[123] On October 25, 2023, it was announced Garrett had purchased a minority ownership stake in the Cleveland Cavaliers of the National Basketball Association (NBA).