Vick resumed his starting role after missing three games with a rib injury and provided the difference for the Eagles (5-3). His TD run with 13:47 to go in the game put Philadelphia up 26-17.
He completed 17-of-29 passes for 218 yards and a touchdown and carried the ball 10 times for 74 yards in the victory -- the Eagles' 12th straight after a bye week under Coach Andy Reid.
Asante Samuel sealed the win with an interception in the final seconds after the Colts had pulled to within two points on a 1-yard Javarris James TD run.
Peyton Manning couldn't keep the the Colts' three-game winning streak alive, going 30-of-51 through the air for 287 yards, one touchdown and two interceptions.
Indianapolis (5-3) also got 10 receptions for 101 yards and a touchdown from Jacob Tamme.