Orlovsky drove the Colts 78 yards to the winning score in 12 plays over 97 seconds. Indianapolis won for the second straight week after losing its first 13 games of the season.
The back-to-back wins have jeopardized the Colts' chances of obtaining the No. 1 pick in the 2012 draft. A loss to the Texans Thursday would have guaranteed the first choice for Indianapolis.
The Texans (10-5), already assured the AFC South title and the first playoff appearance in franchise history, saw their hopes for a first-round bye diminish. Pittsburgh and Baltimore are tied for the lead in the AFC North at 10-4 and the winner of that division will likely be in position to secure the No. 2 seed behind New England.
With Indianapolis quarterback Peyton Manning having been out all season following neck surgery, Orlovsky made his seventh appearance of the campaign. It became a memorable one when he executed the 2-minute offense to perfection -- converting on two third downs along the way.
Indianapolis benefited from a pass interference call on 3rd-and-5 from the Houston 6-yard line. That penalty put the ball on the Texans' 1 and Orlovsky then lofted a pass to Wayne for the touchdown.
It was the only Indianapolis touchdown of the game. The other Indianapolis points came on field goals of 23, 32, 47 and 31 yards by Adam Vinatieri.
Houston's lone touchdown came on a 9-yard run by Arian Foster in the first period.
Orlovsky completed 23-of-41 passes for 244 yards without an interception.
Houston rookie T.J. Yates was 13-of-16 for 132 yards. The Texans attempted to get the win primarily through the running game with Foster picking up 158 yards on 23 carries.