Mack suffered the injury after catching an underneath pass in the second quarter. He immediately grabbed his ankle, got up and took off his helmet before waving for assistance from the Colts' sideline.
Mack's injury comes in the final year of his contract. The Colts did not offer him a contract extension during the offseason.
Mack, who rushed for a career-high 1,091 yards in 2019, missed at least two games in each of his first three seasons with the Colts.
Depth at running back is not a problem for the Colts. Nyheim Hines, who had two touchdowns in the first half, and rookie Jonathan Taylor became the primary running backs after Mack left the game. The Colts also have Jordan Wilkins in the backfield, as they have made running the ball a priority.
"I know [Mack's] going to be in not only my ear but the rest of the backs' ear until he gets back -- whatever his status is -- in order to make sure we can uphold his part and make sure that the running back group is not a dropoff," Taylor said Sunday.