Josh Reddick also homered for Boston — his first of the season — as the Red Sox avoided being swept in Fenway Park by the Orioles for the first time since 1994. Boston has been swept at home twice this season.
The Orioles lost for just the fifth time in 17 games.
Lackey (13-11), who had lost four straight starts for the first time in his career, pitched seven innings. He allowed one run and five hits and struck out four.
The veteran right-hander, signed as a free agent to a $82.5-million, five-year deal during the offseason, was expected to be a top of the rotation pitcher, but he has struggled with inconsistency this season. He's allowed five or more runs in nearly one-third of his starts.
Ortiz hit his three-run homer — his 31st — into the Red Sox bullpen off Kevin Millwood (3-16) to push Boston ahead 3-1 in the fourth inning. The slugger needs four RBIs for sixth career 100-RBI season. He had five for the Red Sox from 2003-07.
Reddick's deep drive into the right-field seats made it 4-1 in the fifth.
Millwood, who has the most losses in the American League, gave up six runs and seven hits in five innings.
Boston closer Jonathan Papelbon pitched a scoreless ninth one night after allowing four runs in a non-save situation.
The Red Sox chased Millwood with two runs in the sixth. Ortiz's RBI single made it 5-1. Adrian Beltre added an RBI double off reliever David Hernandez.
Baltimore took a 1-0 lead in the fourth on Ty Wigginton's RBI double.
Notes
The teams split the season series 9-9. … The Red Sox were swept at home by Tampa Bay in April and the White Sox earlier this month. … Lackey went over 200 innings for the fifth time in his career. … Orioles manager Buck Showalter announced most of his rotation for this weekend in Toronto: RHP Chris Tillman will start Friday, Jeremy Guthrie on Saturday, but he was still undecided for Sunday. … Boston's Ryan Kalish shattered his bat on a single to right and the end went flying about 10 rows back behind the Red Sox on-deck circle, where it was caught by a fan. … Baltimore's Nick Markakis has 43 doubles this year; his fourth straight year with at least that many. He's just the third player in major league history to accomplish that feat. Hall of Famers Joe Medwick (1935-39) and Tris Speaker (1920-23) are the others. … Boston 3B Adrian Beltre needs one RBI for his second career 100-RBI season. The other came with the Los Angeles Dodgers in 2004.