Brees, who played college football 65 miles north of Lucas Oil Stadium at Purdue, completed 28 of 44 passes for 255 yards and a touchdown, and New Orleans defeated the reeling Colts 27-21 Sunday.
Beginning with the 1986 season, the Saints (3-4) are 8-2 against Indianapolis (3-4), including a 31-17 Super Bowl victory on Feb. 7, 2010 in Miami. New Orleans also defeated the Colts 62-7 during the 2011 regular season in New Orleans.
The Saints grabbed a 7-0 lead with 2:31 remaining in the first quarter on a 1-yard run by Khiry Robinson after backup quarterback and holder Luke McCown completed a 25-yard pass to tight end Ben Watson on a fake field goal. Robinson scored on the next play, capping a 10-play, 78-yard drive.
Saints middle linebacker Stephone Anthony set up the next score, intercepting Andrew Luck at the Indianapolis 23-yard line with 2:16 left in the quarter. Five plays later, Robinson ran six yards for his second touchdown and extended the lead to 14-0.
On the ensuing kickoff, Colts return man Griff Whalen fumbled at the Indianapolis 27, and Saints cornerback and special teams player Kyle Wilson recovered. With 13:36 left in the first half, Brees threw a 16-yard touchdown pass to tight end Michael Hoomanawanui. At that point, New Orleans led, 20-0.
The Saints' lead became 27-0 with 10:26 left in the third quarter when Mark Ingram scored on a 1-yard run, capping a six-play, 82-yard drive.
Luck, who was 9 of 19 for 79 yards and two interceptions in the first half, finally got untracked in the third quarter, throwing 87-yard and 46-yard touchdown passes to wide receiver T.Y. Hilton, slicing the deficit to 13 points entering the final 15 minutes.
On each of Luck's touchdown passes to Hilton, Saints cornerback Delvin Breaux fell down. After a miserable first half, Luck was 7 of 10 for 159 yards, 133 of which came on the touchdown passes to Hilton.
The Colts closed to within 27-21 with 3:05 remaining on Luck's 8-yard touchdown pass to wide receiver Donte Moncrief, capping a seven-play, 80-yard drive.
Indianapolis attempted an onside kick after Moncrief's touchdown, but the Saints recovered at their 47-yard line. Brees' 20-yard completion to Marques Colston on third-and-4 moved the ball to the Indianapolis 27-yard line, allowing New Orleans to run out the clock.
Ingram had 144 yards on 14 carries.
NOTES: Colts QB Andrew Luck did not complete his first pass until 9:08 remained in the first half. The Colts had 16 total yards in the first quarter. ... New Orleans exhausted its supply of first-half timeouts with 50 seconds remaining in the first quarter, losing two by virtue of lost challenges ... Indianapolis rookie WR Phillip Dorsett suffered an ankle injury during the second quarter, and while he walked off the field under his own power, he did not return ... Indianapolis C Khaled Holmes suffered a burner in the second quarter and did not return ... The Colts played without starting SS Mike Adams, who suffered a hamstring injury in last week's loss to the New England Patriots.