The Chargers (12-3) won their 10th consecutive game and clinched a first-round playoff bye as champions of the AFC West. It was also San Diego's 18th straight victory in the month of December.
Tennessee (7-8) failed in its bid to keep alive hopes for a winning season after having lost its first six games. The Titans can still achieve a break-even campaign with a win next week at Seattle.
Philip Rivers threw for 264 yards and two touchdowns while leading a relentless San Diego offense that accounted for 425 yards and 30 first downs.
San Diego's first five touchdowns came at the end of drives of 76, 76, 52, 85 and 65 yards.
Tomlinson scored on a pair of 1-yard runs, one of them putting San Diego in front for good at 7-3 late in the first period and the other giving the Chargers a 28-3 advantage in the third.
Sproles caught a 3-yard scoring pass from Rivers in the first half and scored on runs of 9 and 1 yards in the second half.
Tennessee quarterback Vince Young was intercepted twice and fumbled the ball away once. San Diego scored after each of the turnovers.