Clinging to a one-run lead entering the sixth, the White Sox erupted for five runs off the Indians bullpen to put the contest away.
Brent Morel then drew a walk and Rafael Perez came in to pitch. He recorded an out before issuing an intentional pass to Paul Kornerko and then yielding a three-run bomb to Pierzynski.
The White Sox catcher finished 3-for-4 with four RBI and Konerko went 2-for-3 with a pair of runs driven in for Chicago, which swept a rain-shortened two game series from the Tribe.
John Danks (1-1) earned the victory, going 5 2/3 innings through which he allowed four runs on seven hits.
Indians starter Justin Masterson (0-1) was tagged for eight hits over five frames.