Joseph Addai ran for 171 yards and tied a franchise record with four touchdowns to help the Colts beat the Eagles 45-21 on Sunday.
Lenny Moore, Lydell Mitchell and Eric Dickerson are the only other Colts with four touchdowns in a game.
Addai, who had 24 carries, scored three in the first half, doubled his season total.
The Colts rebounded from their first loss of the season, 21-14 to Dallas last week, to improve to 10-1, the best record in the league.
With the win and a win next week against Tennessee, the Colts will clinch the AFC South.
A win also prevented the Colts from losing consecutive games.
Since coach Tony Dungy's arrival in 2002, Indy has lost consecutive games only three times: a three-game skid in the middle of 2002; consecutive losses in October 2004 and two straight late last season, the second of which most starters did not play.
The Colts opened the game with a nine-play, 79-yard drive over 4:54 that ended with Addai's 15-yard touchdown run.
Philadelphia answered with a long drive, but David Akers missed a 36-yard field goal with 1:48 left.
The Colts scored on the ensuing possession. Reggie Wayne's one-handed catch down the left sideline for 36 yards highlighted the drive. The Eagles challenged the call, but it was upheld. Addai later scored his second touchdown, a 10-yard run on the first play of the second quarter, to make it 14-0.
Nick Harper's interception gave the Colts the ball again, and Addai scored his third touchdown, a 15-yarder, for a 21-0 lead with 8:58 left in the half.
Philadelphia finally scored in the closing minutes of the half. L.J. Smith's 1-yard touchdown catch from Jeff Garcia capped a 10-play, 88-yard drive and cut the Colts' lead to 21-7 with 1:19 left in the half.
Peyton Manning led the Colts downfield one last time before the break, and Adam Vinatieri's 44-yard field goal made it 24-7.
Manning completed 10 of 14 passes for 125 yards in the first half. He became the fastest quarterback to 3,000 completions, according to the Elias Sports Bureau. It took him 139 games, seven fewer than Dan Marino and Drew Bledsoe.
Addai continued to do damage early in the third quarter but as a decoy. Manning executed a perfect fake to his running back before finding Wayne alone in the middle of the end zone. The 11-yard pass gave the Colts a 31-7 lead with 6:39 left in the quarter.
Garcia started for Donovan McNabb, who is out for the season with a torn anterior cruciate ligament in his right knee. He will miss the final six games for the second straight season and the third time since 2002.
Garcia was 19-of-23 for 140 yards and threw two touchdowns. Brian Westbrook ran 20 times for 124 yards and one touchdown, becoming the first Eagle since Wilbert Montgomery in 1981 with three consecutive 100-yard games.
NOTABLE: Colts tight end Dallas Clark sprained his right knee while being tackled in the second quarter and did not return. His status is unknown.