Newton was signed by the Carolina Panthers at a ceremony held at Radio City Music Hall that started with boos as commissioner Robert Goodell walked onto the stage.
This pick marked the third straight year a quarterback went first in the draft.
The Panthers finished the 2010 season 2–14 with four quarterbacks in rotation and two of those rookies.
Newton said in an ESPN interview he was shocked to be selected as the No. 1 pick and felt blessed the Panther organization showed faith in him.
"I can't wait to get to my new hometown of Charlotte," Newton said. "I need to get to work. I've heard so many people say it, and you're hearing it straight form the horse's mouth. It's time to get to work now."
Newton might not get the chance to get to work if the NFL wins an appeal to reinstate a lockout that was lifted Monday night, 45 days after it began.
Former Auburn defensive tackle Nick Fairley was also taken in the first round, being selected by the Detroit Lions in the 13th pick.
The Lions finished last season 6–10 and ranked 24th in the NFL for rushing yards allowed per game.
Fairley led Auburn's championship defense, finishing the season with 24 tackles for loss and 11.5 quarterback sacks.