Boston erased a 5-1 deficit against CC Sabathia and defeated the defending World Series champions in the first night opener in the history of 98-year-old Fenway Park.
Jorge Posada and Curtis Granderson hit back-to-back homers off Josh Beckett to give the Yankees a 2-0 lead in the second inning. It was 7-5 in the bottom of the seventh when Marco Scutaro singled and Dustin Pedroia tied it with an Opening-Day homer for the second consecutive season.
Youkilis then doubled with two outs, took third on Damaso Marte's wild pitch and scored when the left-hander's high pitch bounced off Posada's glove. Pedroia added an RBI single in the eighth.
Hideki Okajima pitched a scoreless inning to get the win and Jonathan Papelbon worked the ninth for the save.
Chan Ho Park recorded just two outs while picking up the loss in his Yankees debut. The right-hander was charged with three runs.
Former Red Sox ace Pedro Martinez got a warm greeting when he threw out the ceremonial first pitch.
The real starters didn't do as well.
Sabathia gave up five runs and six hits over 5 1/3 innings in his second poor opening-day start since he joined New York for a $161 million, seven-year contract.
Beckett allowed five runs and eight hits in 4 2/3 innings. It was the worst of five Opening-Day starts for the right-hander.
The Yankees began the season as champions for the first time since they beat Kansas City 7-3 behind Roger Clemens in the 2001 opener. They finished that year in the World Series, but lost to the Arizona Diamondbacks in seven games.
The last time the Red Sox and Yankees met in an opener was in 2005 following Boston's first championship since 1918. New York won 9-2 with Randy Johnson beating David Wells - like Sabathia, a big lefty.
Youkilis got the first hit off Sabathia, a leadoff double in the second, and scored on Adrian Beltre's sacrifice fly. Youkilis then tripled in two runs in the sixth before Beltre's RBI single tied it at 5.
On the first pitch of the major league season, Derek Jeter grounded out to shortstop Scutaro. Nick Johnson then flied to center and Mark Teixeira grounded out to first. Seven pitches, three outs.
The first eight batters of the game were retired before the Yankees, who led the AL last season with 244 homers, got two longballs in a row. Posada hit a short liner off the right-field foul pole. Then Granderson sent a long drive into the center-field seats in his first at-bat as a Yankee.
The Yankees went ahead 7-5 in the seventh on Robinson Cano's RBI groundout and Posada's run-scoring single but Boston responded with three runs in the bottom half, culminating in Youkilis' tiebreaking scamper.