Matthew Stafford led Los Angeles on two late scoring drives and Matt Gay made a tiebreaking field goal with 2:23 to go to give the Rams a 27-24 victory at Indianapolis.
Stafford finished 19 of 30 with 278 yards, two touchdown passes and one interception.
The Colts fell to 0-2 for the first time in coach Frank Reich's four-year tenure.
And it could get worse with a three-game road trip looming and the status of quarterback Carson Wentz in doubt. He left with a right ankle injury midway through the fourth quarter and did not return, dooming Indy's comeback hopes.