The defending National Champion Gamecocks won 5-4 to take two of the series' three games.
David Haselden, who allowed three hits, struck out four in six innings of work and retired nine-straight batters at one point, left Clemson in prime position heading into the final three innings.
But South Carolina's four-run seventh proved to be too costly.
"It was a tough loss for us. David Haselden did a good job for us, for six innings," said Clemson head coach Jack Leggett. "He gave us, maybe, as much or more than we thought."
Haselden pitched an inning in Clemson's emotional 10-5 win on Sunday and felt just fine coming off a day's rest.
"My arm felt good. I got some treatment from our great athletic trainer yesterday, so I was feeling pretty good. I wasn't worried," he said.
There wasn't much cause for concern until the sixth when he walked the leadoff batter Scott Wingo, who was moved over to second on a sacrifice bunt. Haselden then struck out Christian Matthews and forced Jackie Bradley Jr. to pop out to third.
Alex Frederick, the first reliever called out of the Tigers' bullpen, managed to retire just one of the four batters he faced. Peter Mooney chopped an infield single off Shaffer's glove to even the score at 1-1.
Sunday's winning pitcher, Joseph Moorefield, was called in from the bullpen with Frederick's runners at first and second. South Carolina countered with pinch hitter Jake Williams, who hit a two-run homerun on Moorefield's second pitch to give the Gamecocks a 4-1 lead.
South Carolina starter Adam Westmoreland allowed four hits, one run, walked two and struck out one. With a runner on in the sixth, he gave way to Bryan Harper and Forrest Koumas, who retired Jeff Schaus and Schaffer, respectively.
"We had some chances, some opportunities with men on base," Leggett said. "There were a couple of double-plays and men left on base. That was probably the difference in the ball game."
South Carolina added another run in the eighth for Koumas, who pitched 2.1 scoreless innings before allowing the first three Clemson runners to reach base in the ninth.
With the bases loaded, Friday's winning pitcher, Michael Roth, gave up a RBI single to John Hinson, which cut the South Carolina lead to 5-2.
Gamecock closer Matt Price then forced Spencer Kieboom to ground into a double-play, but another runner crossed the plate.
A Will Lamb triple into right field brought Clemson within a run, but Jon McGibbon struck out looking with Lamb 90-feet away from tying the game.
"This team has so much heart," Shaffer said. "We're never going to quit. I don't care if we're down 15 runs in the ninth inning. We're going to give it everything we've got until we run out of outs."
Clemson travels to Western Carolina on Wednesday before heading back home for the ACC opener against Virginia.
Tigers drop rubber match
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