Rookie running back Ameer Abdullah had an immediate impact on his NFL debut for the Lions, running his first carry 28 yards for a touchdown on the first drive of the game.
San Diego tried to level the scores down the other end early on, but Melvin Gordon's knee came down short of the plane, leaving the hosts to kick a field goal.
The Lions looked to be running away with the game when Glover Quin intercepted a Philip Rivers pass shortly after, bringing it back for a second Detroit touchdown, before Matthew Stafford connected with tight end Eric Ebron through the middle to extend the lead further.
The Chargers kept themselves in contention at half time, though, as Danny Woodhead timed a run from just a couple of yards out to sprint over for the home side's opening touchdown of the game, although Rivers was intercepted again in the final seconds of the second quarter while trying to find the endzone for a second time.
San Diego closed the gap further midway through the third quarter when Rivers spotted Stevie Johnson open out wide, firing over the top to connect with the receiver, leaving Detroit just a point ahead.
The AFC West side moved ahead for the first time early in the fourth quarter as Rivers got the ball to Ladarius Green through the middle, but a penalty moved the extra point kick back, preventing Josh Lambo from splitting the uprights.
Abdullah tried to make another lively run to set up a second touchdown of the day on his debut, but a heavy tackle resulted in the running back fumbling the ball, while Stafford could not find Golden Tate for the first down, forcing the Lions to punt.
San Diego made the most of the Lions' stalled drive as they made it back-to-back touchdown possessions with Keenan Allen picking up a couple of big gains before Woodhead punched it in from close range, leaving the hosts 12 points up with just over six minutes still on the clock.
The Lions did make it tight late on as Theo Riddick hauled in a pass from Stafford just inside the endzone, but the quarterback was unable to get the ball back downfield again in the final seconds.
The win ensures that the Chargers have never lost at the Qualcomm Stadium to the Lions, who lose their opening game of the season for the first time since 2010.