The score was tied 2-2 in the fifth when Chicago loaded the bases with one out against Ivan Nova (11-7) and Youkilis followed by smacking a 1-0 pitch over the fence in right-center field, breaking the game open.
Paul Konerko went 2-for-4 with a solo shot while Dewayne Wise added four hits and scored a run for the American League Central-leading White Sox, who clinched their three-game series against AL East-leading New York.
Francisco Liriano (5-10) earned the victory, allowing a pair of runs on six hits over six innings. The left-hander walked three and struck out seven.
Nova ended up allowing six runs on seven hits over six frames.