He played college football for the South Florida Bulls and was selected by the Indianapolis Colts in the fourth round of the 2017 NFL draft.

[2] He totaled 1,666 yards from scrimmage and scored 22 touchdowns on offense, and made 100 tackles and intercepted four passes on defense.

[14][15] During his junior season, Mack became South Florida's all-time leading rushing, passing Andre Hall's 2,731.

[28] Throughout training camp, Mack competed to be the primary backup running back against Robert Turbin and Josh Ferguson.

[29] Head coach Chuck Pagano named Mack the third running back on the Colts’ depth chart to begin the regular season, behind Frank Gore and Turbin.

[30] Mack made his NFL debut in the season-opener at the Los Angeles Rams and had ten carries for 24 yards.

[32] In Week 5, Mack had nine carries for a season-high 91 rushing yards and a touchdown during a 26–23 overtime victory against the San Francisco 49ers.

[35] Mack entered training camp slated as the starting running back after Frank Gore departed in free agency.

[39] On October 28, 2018, Mack ran the ball 25 times for 132 yards and two touchdowns in the Colts 42–28 win at the Oakland Raiders in a Week 8.

He also became just the third player in Colts franchise history to have multiple games with at least 125 yards rushing and two touchdowns in the same season, joining Eric Dickerson (1987) and Edgerrin James (1999 and 2005).

[44] In the Wild Card Round against the Houston Texans, Mack set a franchise postseason record with 148 yards and a touchdown on 24 carries in a 21–7 victory.

[46] During the season-opener against the Los Angeles Chargers, Mack rushed 25 times for 174 yards which included a career-high 63-yard touchdown run in the 24–30 overtime loss.

[49] During Week 11 against the Jacksonville Jaguars, Mack finished with 109 rushing yards and a touchdown before fracturing his hand in the 33–13 win.

[67] On August 9, 2023, head coach Jonathan Gannon announced that Mack would miss the 2023 season due to another torn Achilles.