It began with a protracted standing ovation from the Colts fans just before kick-off and ended with a first loss for the visitors as Manning failed to match the rousing performance of his young successor, Andrew Luck.
The Colts, ably assisted by a defence that sacked their former leader four times as well as intercepting him once, bounced back from a defeat to San Diego with this 39-33 victory, with Luck throwing for three touchdowns before adding a rushing TD of his own in the third quarter.
The Broncos threatened to rally with two fourth-quarter touchdowns but the Colts held their advantage to seal victory for a famous win.
“Hopefully we’ll have a chance to play these guys again because that would mean we made the play-offs,” Manning said.
“I think if there is a next time it may be a little bit easier just because it was somewhat of an emotional week and it can be a little bit draining, I will say that.”
With Denver losing, their divisional rivals the Kansas City Chiefs were given the opportunity to own the last remaining unbeaten record in the AFC.
They didn’t have it all their own way against the injury-riddled Houston Texans, who lost running back Arian Foster and linebacker Brian Cushing during the 17-16 loss.
Meanwhile in the AFC East, the New York Jets beat arch-rivals the New England Patriots at home courtesy of an overtime kick from Nick Folk, which gave the Jets a 30-27 win in dramatic circumstances.
Another showdown between AFC rivals saw the Pittsburgh Steelers edge out the Baltimore Ravens 19-16 at home for just their second victory of the season, a result which leaves the Super Bowl champions in serious peril of not making the post-season.