Matthew Stafford led Los Angeles on two late scoring drives and Matt Gay made a tiebreaking 38-yard field goal with 2:23 to play Sunday, giving the Rams a 27-24 victory.
The Rams have won three straight in this series and have taken all five road openers under coach Sean McVay.
Stafford wasn't as proficient as he was in the season-opening victory over Chicago but he did play well — even after appearing to hit his right thumb on the helmet of Colts defensive tackle DeForest Buckner in the first half. He did not miss a play. He finished 19 of 30 for 278 yards, two TD passes and one interception.
Cooper Kupp caught nine passes for 163 yards and two scores for the Rams (2-0).
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The Colts are 0-2 for the first time in coach Frank Reich’s four-year tenure and now face a daunting three-game road trip.
Indy charged back from a 17-6 deficit to take the lead at 21-17 when Rams long snapper Matt Orzech hit protector Nick Scott in front of punter Johnny Hekker. The ball bounced into the end zone and was recovered by Ashton Dulin.
Stafford only needed four plays to find Kupp for a 10-yard TD pass to make it 24-21.
Indy tied it again on a 35-yard field goal with 7:22 left, but quarterback Carson Wentz injured his right ankle on the play before the field goal and did not return. The injury doomed Indy's comeback hopes as Jacob Eason was intercepted on his second NFL pass.
The Indianapolis Colts welcomed back their newest Hall of Famers, Peyton Manning and Edgerrin James, with a rousing halftime ovation. Both were presented with their Hall of Fame rings and team owner Jim Irsay ordered watches for each player, too.
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Both had returned previously to Lucas Oil Stadium for their inductions into the Colts Ring of Honor.
“Edgerrin never had to go through a 3-13 season," Manning said after the ceremony. “We weren’t very good until he got here. Let’s face it, once he got here, things picked up quickly. It was a fun run. It was a fun time to play. It was a great place to play and the fans were a big part of it."
Rams: Running back Darrell Henderson left the game in the fourth quarter with a rib injury. Rams officials said he was questionable to return but he did not. Stafford appeared to hit his right thumb on the helmet of DeForest Buckner in the first half but did not miss a snap.
Colts: Right tackle Braden Smith (foot), cornerback Xavier Rhodes (calf) and receivers T.Y. Hilton (neck surgery) and Parris Campbell (abdomen) all were inactive.
Rams: Hosts reigning Super Bowl champion Tom Brady next Sunday.
Colts: Visit defending AFC South champ Tennessee next Sunday.