NFL Network's Tom Pelissero reported the confirmation of the Colts' initial fears regarding Mack's injury on Monday.
Mack had four carries for 26 yards before being ruled out for the game.
The running back set a career high with 1,091 rushing yards last season, becoming a reliable weapon for a Colts offense that dealt with plenty of injuries and turnover.
His production came after his breakout 2018 campaign, when he finished with 908 rushing yards and nine touchdowns in 12 games while averaging 4.7 yards per carry. However, durability remains a question mark after the 24-year-old missed at least two games in each of his three seasons.
The fourth-round pick out of South Florida dealt with a broken bone in his hand last season, forcing Indianapolis to look further down the depth chart.
The squad added more depth at the position this offseason with the addition of Jonathan Taylor, the third running back off the board in the 2020 NFL draft. The rookie could take on a bigger workload while Mack is out, potentially showcasing the ability he displayed throughout an incredible career at Wisconsin.
Nyheim Hines should also have a big role after scoring two touchdowns in Sunday's game.