Manuel's first four seasons in the NFL were spent in Buffalo after being drafted 16th overall in the 2013 NFL Draft. He was selected with the hopes of developing into a franchise quarterback for the Bills, but those hopes never materialized. Manuel started just 17 games in four seasons with Buffalo, including being benched in 2014 for journeyman Kyle Orton and losing out in a camp competition in 2015 to Tyrod Taylor. Manuel would start three games while serving as Taylor's backup, but lost all three to end his Bills career.
Manuel's NFL career lasted just five seasons, totaling career numbers of 343-for-590 (58.1%) for 3,767 yards, 20 touchdowns, 16 interceptions and a 6-12 record as a starter.