Coach Frank Reich said Friday that Hilton's calf injury could hold the speedster out multiple weeks.
"With the information that we have, generally speaking, it's a 3-4 week injury," Reich said.
Hilton suffered the calf injury during Wednesday's practice.
Since being drafted in the third round in 2012, Hilton has missed five games. The Colts are 0-5 in those contests, including Week 4's loss to Oakland.
With Hilton slated to miss time, the Colts will lean on Zach Pascal and Chester Rogers as Brissett's top two targets. Dynamic but inconsistent rookie Parris Campbell should also see an uptick in targets coming his way -- he has the talent to be a difference maker if he can put it together. Deon Cain, who has been inactive the past two weeks, could also see time.