Backup quarterback Shaun Hill completed 6, and complete a perfect preseason.
Former Philadelphia Eagle and Cleveland Brown Jerome Harrison led the rushing attack for the Lions. The six-year veteran rushed seven times for 72 yards, including a 47-yard burst.
Kicker Jason Hanson converted three field goals for Detroit.
Tight end J.J. Finley caught two passes for 20 yards, while Maurice Stovall caught a 16-yard touchdown.
Former Clemson star C.J. Spiller rushed twice for 29 yards, while Bruce Hall rushed four times for 25 yards and one score.
Craig Davis hauled in six passes for 38 yards, while Kamar Aiken added two catches for 37 yards.
The Lions opened the scoring in the first quarter when Hill connected on a 16- yard touchdown pass to Stovall to cap a 7-play, 80-yard drive.
In the second quarter, Hanson knocked a 44-yard field goal attempt through the uprights to send the Lions into halftime with a 10-0 lead.
Hanson connected on his second field goal attempt late in the third quarter and his third midway through the fourth to push the advantage to 16-0.
The Bills finally got on the board when Hall bowled his way into the end zone from one yard out late in the final quarter to make it a 16-6 game.