Connor Shaw threw three touchdown passes and 13, in the final regular season game for both squads.
Shaw completed 14-of-20 passes for 210 yards and carried the ball 19 times for 107 yards for the Gamecocks (10-2), who finished the season in second place in the SEC East behind Georgia.
Bruce Ellington, Rory Anderson and Alshon Jeffery each caught a touchdown pass, while Kenny Miles rushed 21 times for 71 yards in the win.
Tajh Boyd threw for 83 yards with a touchdown and an interception on 11-of-29 passing for Clemson (9-3), which will face Virginia Tech next week for the ACC title game.
Up 17-10, the Gamecocks extended their lead on their first touch of the third quarter when Anderson hauled in a 55-yard catch-and-run before finishing the 66-yard drive with a two-yard TD reception.
Later in the third, Clemson started a drive at the South Carolina 36 after Joey Scribner-Howard shanked a punt from inside his own end zone. But the Tigers would only reach as far as the Gamecocks' 14 and Chandler Catanzaro split the uprights from 40 yards out to make it a 24-13 game with 13:48 to go in the fourth.
South Carolina answered with a 14-play drive that lasted over seven minutes, resulting in Wooten's 37-yard kick.
DeVonte Holloman sealed the victory for the Gamecocks three plays later when he stepped in front of a Boyd pass and took the interception 26 yards down to the Clemson 19, setting up Jeffery's 18-yard touchdown grab.
South Carolina took the opening drive down to the Clemson 22, but had to settled for a 47-yard Jay Wooten field goal.
They were able to reach the end zone after a Clemson three-and-out when Shaw hit Ellington in stride deep down the middle of the field for a 49-yard touchdown to take a 10-0 lead in the first quarter.
After trading punts, Clemson was able to get on the board early in the second quarter when Dwayne Allen capped a 12-play, 61-yard drive by catching a short pass to the left side and leaping into the end zone for a nine-yard score.
The Gamecocks were slowed down by a couple of costly penalties on the ensuing drive before Scribner-Howard dropped the snap on his punt attempt and his kick was blocked by Clemson.
The Tigers recovered at the South Carolina 26, but could not push the ball into the end zone and Catanzaro tied the game at 10 with a 32-yard field goal.
South Carolina started its next drive at its own 40 after Clemson's kickoff sailed out of bounds. Miles converted a 4th-and-2 with a seven-yard rush before Shaw capped the nine-play march by rushing up the middle for a 15-yard score to give the Gamecocks a 17-10 lead at the break.
This was the 109th meeting between the teams. Clemson holds a 65-40-4 advantage in the series...South Carolina won 10 games in a season for just the second time in school history (1984)...The Gamecocks extended their regular season non-conference win streak to 12 games.