The AFC East side used the 16th pick of the 2013 NFL draft on the Florida State Seminoles quarterback.
The 23-year-old told the team's website: "I am just so excited. I am so proud to be a Buffalo Bill. I am just proud of family, all of my teammates at Florida St and my coaches who helped me get to this point. I am just extremely proud and happy right now.
"I felt that [general manager Buddy] Nix and the coaches liked me a lot at the Senior Bowl and then when I met with them again at the Combine, I felt the same way. And then also, when I went out and worked out for them. Then I went up for a visit. There was a lot of confirmations going on.
"This goes down as probably the best day, the best night of my life. To be the first quarterback taken in the NFL Draft, to be a first rounder, to be taken by the Buffalo Bills considering where I started from in January to this day now is, I am just so proud and happy for the team I have and the people who helped me get to this point."
Manuel was the only quarterback selected in the first round this year.