Youkilis, who feuded with Red Sox Manager Bobby Valentine before being traded to Chicago last month, lined a shot into the seats above Fenway Park's Green Monster left-field wall with two aboard in fourth inning for a 6-2 Chicago lead.
The third baseman went 3-for-4 Monday in his debut against his ex-teammates, won by Boston 5-1.
Alejandro De Aza added a pair of RBI for American League Central-leading Chicago.
Phil Humber (4-4) came off the disabled list (right elbow flexor strain) to allow two runs on six hits over six innings, walking none while striking out three.
Boston's Jon Lester (5-7) was lit up for six runs on seven hits, lasting only four innings.
Kelly Shoppach smacked a two-run homer while Carl Crawford went 3-for-4 with an RBI and two runs scored for Boston.