Drew Brees set the tone for New Orleans (2-1) with 240 yards passing, including touchdowns to Devery Henderson and Robert Meachem.
Philip Rivers led two touchdown drives for the Chargers (1-2). His 167 yards passing included a 9-yard TD toss to Malcom Floyd. Antonio Gates caught five passes for 66 yards.
The Saints had a scare when starting middle linebacker Jonathan Vilma went down with a right groin injury early in the third quarter. He jogged off the field on his own and Vilma wrote "I'll be fine" on his Twitter account.
Brees was 18 of 27 and looked sharp for the most part, though his longest completion, a 46-yard touchdown to Henderson, looked like and ill-advised throw into coverage that was nearly intercepted.
Cornerback Antoine Cason saw the pass all the way, got inside position and went up for the interception near the goal line, but Henderson swiped from behind to break up the play and wound up tipping the ball to himself in the end zone.
The Chargers are hoping Cason, a 2008 first-round draft pick, can help fill the void left when the Chargers traded Antonio Cromartie to the New York Jets . Cason had a rough night against Brees and the Saints' high-powered offense, though.
He was victimized on New Orleans' second score when he anticipated a throw to the corner of the end zone, only to have Meachem cut underneath for an easy 15-yard catch to make it 14-7.
Brees' highlights including a 21-yard pass down the middle to Jeremy Shockey and a heady backhanded flip to Reggie Bush in the flat for a 38-yard gain that set up Garrett Hartley 's 40-yard field goal in the last minute of the first half. Bush wound up with seven receptions for 70 yards. Marques Colston had 55 yards on four catches.
San Diego's first-team offense put together two scoring drives in the first half. The Chargers opened the game with a balanced, 12-play, 82-yard touchdown drive. Jacob Hester capped it with a powerful 6-yard run on which he stretched across the goal line. Rivers was 5 of 6 for 44 yards on the drive, while first-round draft choice Ryan Mathews gained 32 yards on five carries, highlighted by a 16-yard run.
Journeyman Billy Volek replaced Rivers in the third quarter and was intercepted by Usama Young on a deep pass. He was later intercepted by Leigh Torrence, who went the other way for an 87-yard score in the final seconds.
Former Tulane quarterback Patrick Ramsey backed up Brees and was 10 of 18 for 191 yards and one TD.
The Saints, who have led the NFL in offense in three of the past four seasons, finished with 552 yards.
Saints reserve offensive tackle Zach Strief hurt his right knee, but the severity was not immediately known.
Hartley was perfect on field goal attempts of 40, 27 and 35 yards.
Volek was 9 of 21 for 97 yards. Mathews finished with 43 yards on 13 carries.