Drew Brees threw two touchdown passes to Tre'Quan Smith 2:19 apart in the second quarter, helping the short-handed Saints rally to beat the Lions 35-29.
“Everybody just persevered and we found a way to get a big win," Brees said.
New Orleans (2-2) played after a short night of sleep, coming off its first two-game losing streak in three years and started the game without six injured starters.
Saints fullback Michael Burton had a false positive test for the coronavirus Saturday, leading to another round of tests for players and staff overnight in the Motor City.
“Just a lot of emotions going on because you never want to be a distraction," Burton said. “They had to wake up other guys and test them."
Early in the game at fan-free Ford Field, the Lions (1-3) looked as though they might take advantage of facing a tired team without three starters on both sides of the ball as they led 14-0 lead 4:37 after kickoff.
In the end, Detroit earned the dubious distinction of being the first NFL team to lose six straight games in which it led by double digits, according to the Elias Sports Bureau.
The Lions also joined the 2011 Minnesota Vikings as the two teams in league history to lose three of their first four games after leading by at least 10 points.
New Orleans was the latest team to come back against Detroit, scoring 35 straight points from late in the first period to midway through the third to take control.
“I’m proud of how we got ready to play despite some of the challenges," Saints coach Sean Payton said.
Matthew Stafford ended the Saints’ run with a TD pass to T.J. Hockenson late in the third quarter. The Lions pulled within six points with 3:36 left in the fourth on Adrian Peterson's 5-yard run and Hockenson's 2-point conversion catch.
The Saints took a step toward sealing the win with Brees converting a third-and-5 from his 27 with a 19-yard pass to Smith.
“That was probably the biggest play of the day,” said Smith, the primary receiver on the play. “We really needed a first down. Drew trusted me and I came down with it.”
And to dash any comeback hopes Detroit had, Alvin Kamara ran for 5 yards on a third-and-3 run from midfield.
START STRONG, FINISH WEAK
Stafford capped the opening drive with a TD pass to D'Andre Swift. After Brees' first pass was deflected and intercepted on his first snap, Stafford threw a 15-yard pass to Kenny Golladay to give Detroit its third double-digit lead that wasn't large enough.
The Lions lost a 17-point, fourth-quarter lead the opener against Chicago. In Week 2, they were ahead by 11 points against Green Bay before giving up 31 straight points and losing an 11th straight game.
Detroit bounced back to beat Arizona with a game-ending drive last week, but embattled coach Matt Patricia fell to 10-25-1 after his team collapsed again. Patricia may have a lot of questions to answer from ownership during the bye week to keep his job.
“Let’s just talk about the Saints game," Patricia said when asked if he was concerned about his job security.
The 41-year-old Brees, without injured receiver Michael Thomas, spread the ball around as he found soft spots in zone coverage. He also had the benefit of a ground game that moved the ball easily against one of the NFL's worst defenses against the run.
Brees was 19 of 25 for 246 yards with two TDs and an interception.
“Drew was outstanding," Payton said. “We had them guessing for most of the first half of the game. Our guys up front did a really good job at the line of scrimmage."
Kamara accounted for 83 yards on the ground and a seventh TD this season. Latavius Murray had 64 yards rushing and two scores.
COMING UP SHORT
Stafford was 17 of 31 for 206 yards with three TDs and an interception on a pass intended for Hockenson in the end zone late in the first half.
“I wish I would’ve thrown it a couple yards further," Stafford said. “I just underthrew it.”
Saints: OT Ryan Ramczyk left with a concussion. Wide receiver and returner Deonte Harris left with an undisclosed injury. Thomas, who practiced during the week, missed a third straight game with an ankle injury. DE Marcus Davenport (elbow, toe), CB Marshon Lattimore (hamstring), CB Janoris Jenkins (shoulder), TE Jared Cook (groin) and LG Andrus Peat (ankle) were also inactive.
Lions: CB Desmond Trufant was active for the first time since Week 1, but went out in the third quarter after aggravating injured right hamstring and didn't return. DT Nick Williams left with a shoulder injury.
Saints: Host the Los Angeles Chargers on Monday, Oct. 12.
Lions: Bye week.
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