Edgerrin James assisted with 143 yards rushing on 23 carries and three touchdowns and Peyton Manning had two touchdown passes, including a record-setter to Marvin Harrison.
The Rams, playing without the ailing coach, Mike Martz, lost the quarterback Marc Bulger to a sprained shoulder in the second quarter after he led St Louis to the early lead. St Louis were coached by the assistant head coach, Joe Vitt, with Martz out indefinitely with a bacterial infection of the heart valve.
Early on, it was almost all defense for Indianapolis. Dwight Freeney chipped in with a forced fumble for the Colts and Robert Mathis took over the NFL sack lead with seven - he has at least one in every game this season. That provided the field position that allowed Indianapolis to run 36 consecutive plays in St Louis territory in the last 27 minutes of the game.
Bulger, who was six-of-eight for 121 yards and a touchdown, was hurt when he was blocked by David Thornton on the first of the interceptions by June, a third-year linebacker who leads the NFL with five picks. It came less than three minutes into the second quarter and led to James' eight-yard touchdown run.
Jamie Martin took over at quarterback for the Rams and could do little but throw underneath until late in the game. He threw a nine-yard touchdown pass to Cam Cleeland for a meaningless score that made it 45-28.
Steven Jackson, who had 46 yards in a 162-yard first quarter for the Rams could do little after that, finishing with 88 yards on 17 carries. St Louis had just over 100 yards in the second and third quarters, when the Colts made their run.
Manning finished 22-of-32 for 191 yards. His six-yard touchdown pass to Harrison with 9min 25sec left in the game set a record of 86 touchdowns for a passer-receiver combination. Manning and Harrison had been level on 85 with San Francisco's Steve Young and Jerry Rice.
The Rams took the early lead on a 21-yard run by Jackson on the first series of the game; a 29-yard field goal by Jeff Wilkins; and a 57-yard touchdown pass from Bulger to Kevin Curtis. Indianapolis came back with second-quarter touchdowns. James went in from a yard out on a drive set up by June's interception - the play on which Bulger was hurt. Then Manning found Reggie Wayne from three yards at the end of an 86-yard touchdown drive to cut it to 17-14. Wilkins' 49-yard field goal ended the scoring.