The Boston Red Sox star added No. 495 an inning later.
The slugger connected again in the third for a long, two-run shot to left. It was his fifth homer of the season and third in six days off Mussina. It also gave Ramirez 13 hits in his past 26 at-bats against Mussina, with four homers and 11 RBIs.
Ramirez, who grew up minutes from Yankee Stadium, has 55 homers against New York. Jimmie Foxx (70) and Ted Williams (62) are the only players with more.
Ramirez has homered at Yankee Stadium in 10 consecutive seasons. He has 29 home runs at the ballpark, which is in its final season before the team moves into a new stadium under construction across the street.