Ortiz reached the milestone with his second homer in Saturday night's game at Tampa Bay. He lined a shot to right center on a 2-2 pitch from Matt Moore leading off the fifth after connecting for No. 499 in the first.
Big Papi has 50 multihomer games in a 19-year career.
Ortiz pumped his right arm as he ran toward first base. His teammates emptied the dugout and bullpen to celebrate the big hit with him.
The designated hitter connected in the first on a 1-2 pitch from Moore in the first, a towering three-run shot into the right field stands.
Ortiz has eight homers in his last 14 games, and 34 this season to became the fourth player to reach the milestone while playing for the Red Sox. He joins Jimmie Foxx (1940), Ted Williams (1960) and Manny Ramirez (2008), who also hit their 500th homer on the road.