A senior who has started 18 consecutive games, Brantley twisted his knee and ankle on a sack just before halftime. He was helped to the locker room and did not return for the second half.
Brantley, who has made positive strides under first-year offensive coordinator Charlie Weis, was relieved by true freshman Jeff Driskel in the Alabama game.
Driskel completed two of his six passes for 14 yards as Florida lost 38-10.
"When we lost John, that took the wind out of our sails," Florida coach Will Muschamp said after the game.
Joe Schad is ESPN's college football reporter. Information from The Associated Press was used in this report.