Stafford amassed 373 aerial yards, 102 of them to Calvin Johnson, who hauled down four passes, including a score, for the Lions (10-5).
Kevin Smith ran for 49 yards and a touchdown on 15 carries for Detroit, which posted its first 10-win season in 16 years.
The Chargers, meanwhile, fell to 7-8, one game off the pace in the AFL West with one week remaining.
Philip Rivers racked up 299 yards on 28-of-53 passing efficiency with one touchdown and two interceptions as San Diego's three-game winning streak was snapped.
Malcom Floyd led the Chargers with 95 yards on six grabs, including a touchdown.