LaDainian Tomlinson scored on a pair of short runs after turnovers to spoil the Cardinals' home opener.
The Chargers improved to 3-0 under coach Marty Schottenheimer, but also started the 2001 season with three wins under former coach Mike Riley before collapsing in the second half of the campaign.
Defensive end Marcellus Wiley had a 40-yard interception return, which led to Tomlinson's four-yard touchdown run with four seconds left in the first quarter.
"That is the only place they would throw it to me on that slant route," Wiley said. "I just checked with the run and then just dropped back. When the ball came to me, I almost wish it wasn't me because it was coming right at me."
"They're a good defense," Arizona coach Dave McGinnis said. "Nobody else has moved it much on them either. But we need to execute regardless of who we're playing."
The Cardinals moved to midfield on their next drive, but Thomas Jones fumbled at the San Diego 43 and cornerback Ryan McNeil recovered. Tomlinson soon made it 14-7 with a two-yard run with 5:03 left in the first half. He carried 26 times for 91 yards and caught five passes for 25.
Arizona had a chance to tie the game in the fourth quarter after safety Justin Lucas intercepted a pass by Drew Brees at the Arizona 38. The Cardinals drove to the San Diego nine after a 27-yard run by Jones at the two-minute warning.
But the Cards went for four passes in the end zone. The first by Arizona's Jake Plummer was batted down, but the second was dropped by tight end Freddie Jones in the right corner of the end zone. On the next two downs, Plummer overthrew MarTay Jenkins and fullback Marcel Shipp.
With the exception of his 27-yard run, Jones was very quiet. After rushing for a career-high 173 yards in last week's win over Seattle, he was held to 73 yards on 17 attempts.
"Our gameplan was the shut down the running game," Edwards said. "We wanted to shut down Thomas. If they can run the ball the ball that sets up everything else. Our defense prides ourselves on turnovers. We try to win the turnover ratio."
The Chargers took a 16-7 lead when Carlos Polk blocked a punt out of the end zone for a safety early in the fourth quarter.
On Arizona's next drive, Plummer was intially picked off by cornerback Alex Molden. McGinnis challenged the call and had it reversed. Two plays later Edwards stepped in front of Freddie Jones and raced in for a touchdown.
Following Edwards' interception, Plummer worked out of the shotgun formation and directed a five-play, 80-yard drive that ended with a 31-yard pass to Shipp with 9:30 left. Plummer threw to Frank Sanders for the two-point conversion, pulling the Cards within 23-15.
The Chargers sacked Plummer three times, increasing their league-leading total to 16. They surrendered their first touchdown of the season as the Cardinals had 297 yards in total offense.
Plummer completed 17 of 36 passes for 229 yards while Brees was 17 of 31 for 181 yards.
"They've shown good defense against the run," Plummer said. "But Houston had some big runs early against them, so we knew we could get it done if we had to run the ball. But we knew throwing it was probably the way we were going to move the ball in chunks and that's what we set out to do."