The Oklahoma quarterback passed for 4,627 yards and 43 touchdowns this season to claim the honor, which is given to the nation's top college quarterback. It is the only award to consider postseason performances in voting by a national media panel as well as Archie, Peyton and Eli Manning.
Mayfield led the Sooners to a Big 12 championship and a semifinal berth in the College Football Playoff.
"To say he took a different path to success would be an understatement," Archie Manning said in a statement. "I doubt there's ever been a player who walked on to two different teams and reached this level of success."
Mayfield left Texas Tech due to communication issues with the coaching staff and then enrolled at Oklahoma in January 2014. He joined the Sooners as a walk-on a month later and was named the starting quarterback for 2015.
Mayfield won the Manning Award over the following finalists: Ohio State's J.T. Barrett, Clemson's Kelly Bryant, USC's Sam Darnold, Alabama's Jalen Hurts, Louisville's Lamar Jackson, Penn State's Trace McSorley, Central Florida's McKenzie Milton, Oklahoma State's Mason Rudolph, Auburn's Jarrett Stidham and Arizona's Khalil Tate.
Former Clemson star Deshaun Watson was the recipient of the previous two Manning Awards.