Clemson (14-4, 3-0 ACC) matched Duke's four-run first inning and followed the Blue Devils' two-run third with three runs in the bottom of that inning. Two insurance runs in the fifth put the game out of reach.
After starter Alan Farina gave up six runs, five Clemson relievers combined for seven scoreless innings. Matt Vaughn (1-0) picked up the win with three strike outs and just two hits in four innings work.
Jonathan Foreman (1-1) gave up seven runs on six hits in 2 1/3 innings to take the loss.
Duke was led by Brett Bartles with a three-run homer and Matt Williams, who added two hits and one RBI.