He played college football for the Florida State Seminoles, leading them to an Atlantic Coast Conference (ACC) championship and Orange Bowl win in his senior year.

Manuel took over for an injured Christian Ponder as the 4–5 Seminoles were in danger of finishing with a losing record for the first time since Bobby Bowden took over the program.

He completed 15-of-20 passes for 220 yards with one touchdown, leading the Seminoles to a 41–28 win over Wake Forest, who at the time had won three games in a row against Florida State.

[10] Florida State entered the Gator Bowl 6–6 and in serious danger of letting legendary coach Bobby Bowden leave with a losing record.

Manuel led Florida State to a 33–21 victory over the West Virginia Mountaineers and won the Gator Bowl MVP honors.

[13] He also led the Seminoles to a victory in the 2010 Chick-fil-A Bowl against South Carolina in relief of Christian Ponder, who was injured in the second quarter of the game.

[16] He helped lead the Seminoles to a comeback win against the Notre Dame Fighting Irish in the Champs Sports Bowl by throwing for 249 yards and two touchdowns.

[22] While Manuel possessed the blue-chip physical characteristics, work ethic, and leadership qualities necessary to be successful at the NFL level, he was faulted for somewhat inconsistent play at times during his college career.

He led a nine-play, 80-yard touchdown march to bring his team back from a six-point deficit in the fourth quarter, with seconds left in the game.

[32] On October 3, during the third quarter against the Cleveland Browns, Manuel sprained his right lateral collateral ligament, causing him to miss the next five weeks of his rookie season.

On September 28, 2014, in a game against the Houston Texans, one of Manuel's passes was intercepted by All-Pro defensive end J. J. Watt and returned 80 yards for a touchdown.

[36] The next day, he was benched in favor of veteran quarterback Kyle Orton after starting the first four games of the 2014 season and bringing the Bills to a 2–2 record.

[42] Against the Jacksonville Jaguars on October 25 in London, Manuel threw for 298 yards and two touchdowns but had three costly turnovers, two of which were returned directly for scores in the second quarter.

However, Jacksonville regained the lead with a Blake Bortles touchdown pass to wide receiver Allen Hurns, sealing the win 34–31 as the Bills were unable to respond.

With the Bills being out of playoff contention, Manuel started the final game of the regular season due to Tyrod Taylor being inactive.

[47] During Week 4 game against the Denver Broncos, Derek Carr suffered a back injury in the third quarter and was relieved by Manuel, who completed 11 of 17 passes for 106 yards and an interception as the Raiders lost by a score of 16–10.

[48] Due to Carr's injury, Manuel started the Week 5 game against the Baltimore Ravens, completing 13 of 26 passes for 159 yards and a touchdown as the Raiders lost by a score of 30–17.