Pierzynski came up to hit for Tyler Flowers and belted a 2-0 pitch deep into right-center field. The ball just cleared the fence for a two-run, go-ahead shot.
The blast marked the fifth straight game in which Pierzynski has homered, tying a White Sox club record.
Kevin Youkilis also homered for American League Central-leading Chicago, which stayed 1 1/2 games ahead of second-place Detroit in the division standings.
Nate Jones (5-0) earned the win in relief of starter Francisco Liriano, while Addison Reed notched his 19th save.