Brees threw for 359 yards and two touchdowns, including a nearly flawless final drive in which he completed 8 of 9 passes for 80 yards to take back momentum after Newton and the Panthers (1-4) had taken their first lead early in the fourth quarter.
The Saints' defense finally sealed the win, letting the Panthers reach only midfield before Newton's desperation heave downfield fell incomplete for the game's the final play.
Newton threw for 224 yards and two touchdowns, including the go-ahead 5-yard scoring pass to Greg Olsen for a 27-23 lead with 12:32 to play. He also scored on a sneak late in the third quarter.
Mark Ingram also ran for a second-quarter touchdown for the Saints (4-1), while Brees found Jed Collins for a short scoring pass about a minute into the game. But Brees' biggest target was tight end Jimmy Graham, who had eight catches for 129 yards and repeatedly beat undersized defenders to the ball.
In addition, Saints kicker John Kasay -- who was on the first Panthers squad in 1995 and stayed with the team until last season -- had three field goals in his return to Charlotte.
Newton seemed poised to deliver an impressive win against Brees and the Saints, starting when he bulled his way through a pile up at the goal line for a 1-yard keeper late in the third that cut New Orleans' lead to 23-20.
Then, after Brees' high pass for Graham bounced off the tight end's outstretched right arm and into the arms of Sherrod Martin, Newton came through again. This time, with the Panthers facing a third-and-goal, he zipped a pass to Olsen just inside the goal line for the 5-yard TD and the 27-23 lead.
Newton even got the ball back with the lead and a chance to work on the clock with about 10 minutes left. But the Panthers managed to burn only three minutes and reach midfield before punting back to the Saints -- and Brees made them pay.
The game had a near fight when Newton found Steve Smith for a 54-yard touchdown in the first quarter.
Newton stepped up in the pocket -- aided by a block from Jonathan Stewart that flipped blitzer Jonathan Vilma over his shoulder -- and fired a high pass downfield to Smith. Smith jumped to beat cornerback Jabari Greer to the pass, knocking Greer to the ground and giving Smith an easy 30-yard run to the end zone.
But as Smith coasted the final 5 yards and crossed the goal line, safety Roman Harper sprinted in on the left side and leveled Smith with a hard hit.
Smith immediately jumped up and flipped the ball to the turf defiantly while players from both sides ran down and began shoving each other. Smith then locked up with Saints safety Malcolm Jenkins, shoving him to the ground and standing over him while holding a firm grip on Jenkins' facemask before the scuffle finally ended.
Harper's late hit was the only penalty called, though it did seem to give a little more spark to the Panthers and a relatively quiet home crowd.