Chris Thompson ran for 147 yards and a touchdown and Dustin Hopkins kicked four field goals for the No. 23 Seminoles (10-4), who reached 10 wins for the first time since 2003.
Manuel took over for senior quarterback Christian Ponder, who left early in the second quarter with a concussion. No. 19 South Carolina lost running back Marcus Lattimore when he was hit hard on the Gamecocks' first drive.
South Carolina (9-5), which was seeking its first 10-win season since 1984, committed five turnovers. Stephen Garcia threw three first-half interceptions and Lattimore and Alshon Jeffery lost fumbles to leave the Gamecocks trailing 16-3 in the third quarter.
Garcia recovered to lead two long touchdown drives that trimmed Florida State's lead to 19-17 before Manuel answered with the 7-yard scoring pass to Taiwan Easterling.
Florida State cornerback Greg Reid, whose hits caused the fumbles by Lattimore and Jeffery, deflected a fourth-down pass by Garcia with 3:23 remaining.
The Seminoles answered with Hopkins' fourth field goal, from 45 yards, to push the lead to nine.
Garcia responded by leading a 79-yard drive, capped by Brian Maddox's 7-yard TD run that made it 19-17. Garcia helped set up the score with a 29-yard pass to Jeffery.
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