As Oakland Athletics public address announcer Dick Callahan mentioned Ortiz's milestone while introducing him in the sixth inning Wednesday, the home crowd rose to give him a standing ovation.
"That was pretty cool," said Ortiz, who removed his helmet and waved to the crowd. "You're playing on the road, and you get something like that done on the road and people really appreciate it."
Ortiz became the 49th player in major league history to reach 400 home runs. He's among eight active players with at least 400 and becomes the second player this season to reach the milestone. White Sox first baseman Paul Konerko accomplished the feat in April, also in Oakland.
Ortiz's homer forged a 1-1 tie in the fourth inning, but Oakland went on to a 3-2 victory to complete a three-game series sweep of the Red Sox.
"It was a big situation to tie the game," Ortiz said. "I'm happy to just get it out of the way. I was very excited."
Ortiz had gone 25 at-bats since his last homer, which came June 27 against the Toronto Blue Jays at Fenway Park.
"(I've) been able to take a lot of swings this past road trip and just keep on leaving the ball on the warning track," Ortiz said. "But to be honest with you, I was not worried about that. I was just swinging like I normally do and not trying to do too much. You see pitchers, how they approach it, I guess they don't want to show up on ESPN."
The blast, a no-doubter to right field, came on a 2-0 pitch from Oakland's A.J. Griffin.
"It was awesome," Red Sox outfielder Cody Ross said. "Of course, everyone's just waiting for it. It seems like every pitch, he's got that chance to do it. As soon as it went in the air, it's just that sigh of relief, I know for him especially, to get that weight off his shoulder. I'm just so happy for him, proud of him. It's a huge accomplishment."
Ortiz is the sixth player to reach 400 home runs while in a Red Sox uniform and the first since Manny Ramirez in 2005. He's the fourth Red Sox player to hit a milestone home run against the Athletics. Jimmie Foxx hit No. 500, and Ted Williams and Carl Yastrzemski both hit No. 400 against the A's.
Griffin became the 273rd pitcher to surrender a homer to Ortiz. It was the 21st home run he's hit against the A's and the eighth in Oakland.
Red Sox manager Bobby Valentine was disappointed Ortiz couldn't enjoy the milestone more after the loss capped a 2-5 road trip.
"I wish he could celebrate more," Valentine said. "David's a team guy. He knows it's a great individual accomplishment. We all know that. It's tarnished (by the loss)."
Jimmy Durkin is a contributor to ESPNBoston.com.