As often seems to happen in big games, both offenses were a bit slow out of the gate, with a pair of three-and-outs and a four-and-out between them.
But Denver's second possession started in prime position at their 44-yard line, and it took them only two plays to take the lead. Manning hit Eric Decker for 39 and 17 yards, and the Broncos were up 7-0 halfway through the first quarter.
A ten-play drive brought Indy as close as the Denver two-yard line, but a Terrance Knighton sack on third-and-goal forced the Colts to settle for a 27-yard field goal.
Two punts later, disaster struck, as Trindon Holliday fumbled a return and gave Indy the ball at the 11-yard line, after a review. Had the play been called correctly the first time, the Colts would have had a touchdown on the fumble return.
For Indy, the officiating error was of no consequence, as on the next snap, Luck hit former Raiders wideout Darrius Heyward-Bey for an 11-yard catch-and-run score, putting the Colts ahead 10-7.
Holliday partially redeemed his massive error by returning the ensuing kickoff 56 yards, setting Denver up one yard shy of midfield.
Manning & Co. took it from there, capping an eight-play drive with a 12-yard pass to Julius Thomas, whose eighth touchdown catch of the season put the Broncos back up 14-10. Orange Julius has scored at least once in six of Denver's seven games, with the Philly game the lone exception.
Although the Broncos forced a three-and-out moments later, a holding penalty on the Colts' punt pinned Denver at their own six-yard line, and a Robert Mathis sack of Manning resulted in a fumble and safety, drawing Indy to within 14-12.
Luck and the Colts took that momentum and added a 66-yard scoring drive, with Stanley Havili's 20-yard touchdown putting Indy back up by 19-14.
Denver forced a three-and-out on Indy's next possession, but it was an expensive victory, as Champ Bailey aggravated the foot injury that had cost him the season's first five games.
Inside the two-minute warning, the Colts again got the ball in prime field position, and they cashed in with a 50-yard drive, with Luck hitting his Stanford buddy Coby Fleener for an eight-yard score that stretched Indy's lead to 26-14 at halftime.
Uncharacteristically, the Broncos opened the second half with a trio of three-and-outs, giving them six on the night.
Indy didn't fare much better, until two 15-yard penalties on Denver helped them expand their lead to 33-14 on a ten-yard scramble from Luck.
Denver's offense finally came to life, but their 67-yard drive stalled out, and the Broncos settled for a 31-yarder from Matt Prater that got them to within 33-17.
The Colts came right back with a 52-yarder from Adam Vinatieri to restore their 19-point advantage, and things looked bleak for Denver.
Denver's defense delivered an enormous play two snaps later, as Duke Ihenacho recovered a fumble by Trent Richardson at the Indy 23-yard line.
Eight plays (and one fine decision by John Fox to go for it on 4th-and-1 from the 14) later, Knowshon Moreno punched it in from the one, and Denver was within 36-30.
Although Denver would force a three-and-out, Manning's arm got hit on his first-down throw, and the result was an interception by Pat Angerer that gave Indy the ball at the 20-yard line.
Vinatieri's 42-yard FG put the Colts back up by two scores at 39-30, magnifying Thomas's dropped two-pointer.
Manning led the Broncos on a furious eight-play, 82-yard drive, but a fumble by Ronnie Hillman finished off Denver's slim hopes.
Matt Prater added a 47-yard field goal with 12 seconds left, but his onside kick went out of bounds, and the Broncos were handed their first loss on the season.
With that, Denver's 17-game regular-season winning streak ended, and the Broncos, at 6-1, are now a game behind the Chiefs, who eked out a 17-16 victory over Houston earlier in the day.
Next Sunday, Mike Shanahan makes his return to Denver, while the Chiefs will host the Browns.
- Manning now has four turnovers and a safety in his past two games, although four of those five plays can easily be pinned on Manny Ramirez (two poor snaps last week), Chris Clark (getting turnstiled by Robert Mathis on tonight's safety), and Julius Thomas (whiffing a block on Angerer's pick)
- Peyton's three TD passes give him 25 on the season and leave him on pace for 57 on the season
- Welker, who was a non-factor for much of the game, went without a touchdown for the first time all year
- Von Miller had only two tackles in his season debut, including one for a loss
- Shaun Phillips had one sack, giving him 6.5 on the year and maintaining his team lead
- Needing 32 points to break the Rams' NFL record for most points through seven games, Denver got 33