Brady had three touchdown passes and tied for the third most yards passing in club history, going 31 of 40 with no interceptions as the Patriots (2-0) scored on each of their four first-half possessions.
The Chargers (1-1) turned the ball over inside the Patriots 35-yard line three times, leading to 17 points. They also were stopped on a fourth-and-goal at the 1, and the Patriots started a 99-yard drive that ended with one of Brady's two scoring passes to Rob Gronkowski.
Philip Rivers threw for 378 yards for the Chargers. They had four turnovers for the second straight year against New England after losing 23-20 in 2010 when the Patriots gained just 179 yards.
Vince Wilfork, the Patriots' 325-pound defensive tackle, got his first career interception to halt a promising Chargers drive late in the first half, rumbling 28 yards on the return.
For the second straight game, New England had a 99-yard touchdown drive. After Stephen Gostkowski's 22-yard field goal made it 10-7, the Patriots got the ball back at their 1-yard line when Jerod Mayo stopped Mike Tolbert short of the goal line.
In the 38-24 win over Miami in the opener, the Patriots also took the ball over at the 1, and Brady and Wes Welker hooked up for a 99-yard touchdown on the next play. This time Brady needed 10 plays to score, completing the drive with a 10-yard touchdown pass to Gronkowski for a 17-7 lead.
San Diego wasted an opportunity on its next series when it reached the Patriots 29 before Wilfork made his interception. That set up a 47-yard field goal by Gostkowski on the last play of the first half, putting the Patriots on top 20-7.
After a scoreless third quarter, the Chargers made it 20-14 on a 3-yard scoring pass from Rivers to Vincent Jackson with 13:33 left.
Then the Patriots made a curious — and potentially costly — decision on fourth-and-4 at the San Diego 49. Rather than have Zoltan Mesko, who hurt his knee on his previous punt, kick the ball, the Patriots went for a first down and failed on Brady's incomplete pass to Deion Branch.
But just three plays later, New England's defense came through when Mayo forced a fumble and linebacker Rob Ninkovich recovered at the Patriots 39. Brady needed just four plays to cover 69 yards and throw a 17-yard touchdown pass to Gronkowski. Danny Woodhead ran in for the two-point conversion and a 28-14 lead.
The Chargers came back, scoring just three minutes later on Rivers' 26-yard pass to Jackson with 5:40 to go. But the Patriots responded with a 16-yard touchdown run by BenJarvus Green-Ellis.