In 2015, he became the first player in NFL history to be selected first-team All-Pro at two different positions, defensive end and outside linebacker, in the same season.

In 2018, Mack was traded to the Chicago Bears for two first-round draft picks and signed a six-year, $141 million extension, becoming the highest-paid defensive player in NFL history at the time.

For the majority of his athletic career, Mack had been relying on basketball to get him a college scholarship, but his plans were dashed by a tear in his patella tendon before his sophomore season.

After this injury, his high school football coach, Waides Ashmon, recruited him to the sport, promising Mack and his parents that it would earn him a scholarship.

[8][9] After redshirting as a freshman in 2009, Mack broke into the starting lineup and was one of the most productive defenders in the Mid-American Conference (MAC).

He recorded 64 total tackles, including 20+1⁄2 for loss (third best in the nation), 5+1⁄2 sacks, one interception, two pass breakups, thirteen quarterback hurries, and five forced fumbles.

[36] After signing a four-year contract worth $18.67 million guaranteed,[37] Mack made his NFL debut in the season-opener against the Jets, recording six tackles in the 19–14 loss.

[39] During a Week 11 13–6 road loss to the San Diego Chargers, Mack recorded five tackles and his first career sack on Philip Rivers.

[41] Mack finished his rookie year with 76 combined tackles (59 solo), four sacks, a forced fumble, and three pass deflections in 16 games.

[45] However, Mack was named the Defensive Rookie of the Year by analysts on ESPN's NFL Live[46] and was one of three linebackers selected to USA Football's sixth annual All-Fundamentals Team (the others being All-Pro veterans Luke Kuechly of the Carolina Panthers and Tamba Hali of the Kansas City Chiefs).

[52] During a Week 3 27–20 road victory over the Cleveland Browns, Mack recorded four tackles and his first two sacks of the season on Josh McCown.

[54] In the next game against the Tennessee Titans, Mack recorded six tackles and another two sacks on rookie Marcus Mariota during the 24–21 road victory.

[57] The following week, Mack was voted to his first Pro Bowl, along with teammates safety Charles Woodson and fullback Marcel Reece.

[58] Mack finished his second season with 77 combined tackles (57 solo), 15 sacks, two forced fumbles, and two pass deflections in 16 games.

[59] After the conclusion of the season, he became the first player in NFL history to make the AP All-Pro First Team at two positions in the same year: right defensive end and outside linebacker.

[62] In a narrow Week 4 28–27 road victory over the Ravens, Mack recorded six tackles and his first sack of the season on Joe Flacco.

[63] During a Week 8 30–24 overtime road victory over the Tampa Bay Buccaneers, Mack recorded a team-high seven tackles and sacked Jameis Winston twice.

[66] During a narrow Week 12 35–32 victory over the Panthers, Mack recorded his first career interception off a pass by Cam Newton and returned it six yards for his first NFL touchdown.

[68] In the next game against the Buffalo Bills, Mack recorded seven tackles and a strip sack on Tyrod Taylor and recovered the football late in the fourth quarter to seal a 38–24 win.

[71] In the Wild Card Round of the playoffs against the Houston Texans, Mack recorded a team-high 11 tackles in the 27–14 road loss.

In the second quarter of the game, he recorded a strip-sack on backup quarterback DeShone Kizer, who was playing in relief of Aaron Rodgers due to a knee injury.

In his second game with the Bears, Mack recorded four tackles and a strip-sack of Russell Wilson during a 24–17 Monday Night Football victory over the Seattle Seahawks.

[87] He continued his excellent play the following week, recording five tackles and a strip-sack on Josh Rosen in a narrow 16–14 road victory over the Cardinals.

[93] Mack returned in a Week 10 Thanksgiving matchup against the Lions; in the latter's 34–22 Bears win, he recorded five tackles and sacked Matthew Stafford twice.

[103] During a narrow Week 2 16–14 road victory over the Broncos, Mack recorded a tackle and his first sack of the season on Joe Flacco.

[104] In the next game against the Washington Redskins, he recorded four tackles, two forced fumbles, and sacked Case Keenum twice in a 31–15 road victory.

[105] In a Week 8 matchup against the Los Angeles Chargers, he recorded four tackles, two pass deflections, and his first sack in a month on Philip Rivers in the narrow 17–16 loss.

[112] During a Week 10 19–13 loss to the Vikings, Mack recorded three tackles and his first interception of the season off a pass thrown by Kirk Cousins and returned it 33 yards.

[113] During a Week 14 36–7 victory over the Texans, Mack recorded two tackles and sacked Deshaun Watson in the endzone for a safety and forced a fumble on Duke Johnson that he also recovered.

[12] In 2017, Mack's younger brother LeDarius joined his alma mater, the University at Buffalo, after two years at ASA College in Miami.