Ballard will have surgery on the left ankle injury, which occurred during practice on Friday when he fell to the ground trying to catch a pass and came up unable to put weight on his foot.
The 24-year old appeared in just one game last season before succumbing to a torn ACL in his left knee which also came on a contact-free play in practice. Ballard had fully rehabbed the injury and was expected to contribute to the Colts offense this year.
As a rookie in 2012, Ballard gained 814 rushing yards and another 152 yards receiving while starting 12 games for Indianapolis.
The Colts will rely on remaining running backs Donald Brown and Trent Richardson to handle a greater workload with Ballard unable to play this season.