The Bills held off a late Minnesota comeback bid in an exhibition game that saw Manuel continue to make a case for the starting job.
He went 10-of-12 for 92 yards and threw a 4-yard touchdown pass to Brad Smith early in the third quarter that put the Bills in front 20-3.
Kevin Kolb completed 13-of-21 passes for the Vikings for 111 yards with one interception.
Manuel completed all six of his throws in the drive that led to the touchdown catch by Smith.
Minnesota quarterback Christian Ponder was 5-of-12 for 53 yards in brief action. Star running back Adrian Peterson did not play for the Vikings.
The Bills have won both their exhibition contests. Minnesota is 0-2.