He entered the game with 999 RBIs.
It was also career homer No. 296 for Big Papi, leaving him four shy of another significant round number.
Ortiz declined to speak to the media before leaving Nationals Park, but the Red Sox were more than happy to speak on his behalf.
"He's been a good player for a long time," said Red Sox manager Terry Francona. "When good players play for a long time, they start hitting milestones. What we care about was winning the game tonight. That's what we showed up for, and he helped us do that."
The towering shot to center by Ortiz snapped a 1-0 deficit for the Red Sox en route to a 6-4 win.
For the first two months of the season, Ortiz's epic slump was one of the biggest stories in baseball. But during the month of June, Ortiz has regained his swagger.
Thursday's homer was Ortiz's seventh of the season, and sixth in the past 15 games.
"He's been a huge part of our team," said Red Sox catcher Jason Varitek. "He's swinging the bat well even before he started having results, and I think that's the key."
Without the services of the designated hitter in a National League park, Francona inserted Ortiz into the lineup at first base and moved Kevin Youkilis across the diamond to third. Third baseman Mike Lowell, who has felt some tightness in his surgically repaired right hip of late, was given the night off.
Ortiz didn't play in Tuesday's 11-3 romp over the Nationals.
"What's been a little hard is you get to Interleague, you get a day off, we're trying to keep everybody healthy," Francona said. "The last thing I want to do is get in David's way of getting hot. The only really bad thing is he has to look up and see a lower batting average. He's going to have to live with that for a while, but as long as he doesn't let that drag him down ... his spirits seem good, he's swinging the bat very well. And if we get David Ortiz the last three or four months, what happened the first couple of months won't matter."