Manuel shook off fierce winds at Ralph Wilson Stadium to complete 20-of-28 throws for 245 yards as the Bills (4-7) notched their first victory since Oct. 20.
One defense, Jairus Byrd made two interceptions and DaNorris Searcy returned a pick-off 32 yards for a touchdown.
Geno Smith was limited to just 103 passing yards on 8-of-23 for New York (5-5) before being benched in the fourth quarter.
He was sacked four times and lost a fumble deep in his own territory to set up a Buffalo touchdown.
2014: NFL Cheerleaders [PHOTOS]
Michael Sam cut from the Dallas Cowboys