Luck tossed three touchdown passes and ran for another in the Colts' 39-33 win on Sunday over the Denver Broncos in Manning's return to Lucas Oil Stadium in Indianapolis.
The Colts released Manning, 37, in March, and the quarterback joined the Denver Broncos.
The game marked Manning's return to Indianapolis for the first time since his departure.
The Colts faithful cheered Manning as a tribute video was played when Denver came out of the tunnel prior to the game. Manning waved and thanked the crowd following the conclusion of the video.
"I just look at it as a chance to play football for a great team. I never looked at it as being the guy who replaced Peyton," Luck said.
Luck and Indianapolis' rock solid defence spoiled Manning's night and snapped the Broncos' 17-game regular season winning streak.
Manning was 29-of-49 for 386 yards with three touchdowns and an interception.
"I enjoyed coming back here," Manning said.
"I appreciate the tribute but the game was disappointing for us."
Meanwhile, Alex Smith threw for 240 yards while rushing for a touchdown, and the stingy Kansas City defence helped keep the Chiefs unbeaten with a 17-16 victory over the Houston Texans.
The Chiefs held an injury-plagued Houston offense to a pair of Randy Bullock field goals while sacking back up quarterback Case Keenum five times over the final two quarters to make a 14-10 halftime lead stand up.
The surprising Chiefs improved to 7-0 on the season.
Smith finished an efficient 23-of-34 with an interception, while Jamaal Charles rushed for 86 yards and a touchdown on 21 carries.
In East Rutherford, New Jersey, Nick Folk made the most of a second chance at a game-winning field goal, drilling a 42-yarder with just over five minutes left in overtime to give the New York Jets a 30-27 win over the New England.
Folk at first pulled a 56-yard try wide to the left, but was given a reprieve when Patriots were called for unsportsmanlike conduct for pushing one of their players into a Jets' blocker.
The penalty moved the ball inside the New England 25, and Folk made good on the second attempt to complete New York's comeback from an 11-point halftime deficit.
Cam Newton passed for 204 yards and a touchdown to lead the Carolina Panthers to a 30-15 victory over the St. Louis Rams at Bank of America Stadium.
Other results on Sunday included Atlanta 31-23 over Tampa Bay 23, Washington defeating Chicago 45-41, Dallas downing Philadelphia 17-3, and Buffalo beating Miami 23-21.
Cincinnati accounted for Detroit 27-24, San Diego thumped Jacksonville 24-6, San Francisco strolled past Tennessee 31 -17, Green Bay beat Cleveland 31-13, and Pittsburgh were 19-16 winners over Baltimore.