Detroit quarterback Matthew Stafford, locked in a battle with Daunte Culpepper for the starting position, completed 5-of-9 passes for 81 yards with an interception. Culpepper did not play, having suffered a cut foot in an accident at his home last weekend.
Stafford, the No. 1 choice in this year's draft out of Georgia, finished the exhibition season with 30 completions in 55 attempts for 389 yards and a touchdown. He also threw four interceptions.
The Lions never trailed, scoring on a 1-yard run by Jerome Felton in the first period and a field goal of 32 yards by Billy Cundiff in the fourth. Rian Lindell kicked field goals of 24 and 48 yards for the Bills.
Detroit finished the pre-season with a 3-1 record. The Lions won all four of their exhibition games last year and then lost all 16 regular-season contests. Their overall losing streak of 17 games is two away from the second-longest in NFL history.
The Lions open the season at New Orleans. Buffalo, which wound up 1-4, will begin its campaign at home against Tampa Bay.
Megyn Kelly: Santa Claus and Jesus are both white men
Penelope Cruz named 2013's 'Best Body' by Fitness magazine