Ortiz will also look to prevent Phil Hughes from winning a career high-tying fifth consecutive start Thursday when the right-hander faces his former division rivals for the first time since signing with the Minnesota Twins.
Ortiz hit a pair of home runs for the second straight game Wednesday while leading the Red Sox (20-19) to a 9-4 victory, their seventh in the last eight road matchups with the Twins (18-20).
"He's one of our best hitters. We depend on him and he's locked in right now and it's a good feeling when he's up to bat," first baseman Mike Napoli said.
The Boston slugger is batting .528 with nine homers and 22 RBIs in 13 games at the Twins' home park, which opened in 2010. He's 7 for 10 in this series and is batting .552 with five homers in his last seven games overall.
"It looks like he's got the ball on a tee," Twins manager Ron Gardenhire said. "You can't misfire like that. That's what we're doing, misfiring. We said we were going to pitch him tough. We haven't pitched him tough."
Hughes (4-1, 3.92 ERA) will try to slow Ortiz down while winning five consecutive starts for the first time since May 28-June 19, 2010. Ortiz is 9 for 22 (.409) with two homers and three doubles in his career against the former New York Yankee, but has one single in his last five at-bats in the matchup.
Hughes has a 2.05 ERA in his last four games, issuing one walk in 26 1-3 innings. He scattered eight hits in seven innings and walked none while outdueling Detroit ace Justin Verlander in a 2-1 victory Friday.
Hughes went 0-1 with a 7.20 ERA in his first three starts for the Twins (18-20) before launching his current win streak.
He had a three-game winning streak against Boston snapped in his only start versus the Red Sox last season. He gave up five runs over 4 1-3 innings of an 11-1 loss June 1 and had a miserable relief appearance against them Sept. 6, getting charged with four runs while recording one out in a 12-8 defeat.
Hughes will be opposed by Clay Buchholz (2-3, 6.44), who seeks a fourth consecutive win over Minnesota.
The right-hander has posted a 3.05 ERA in his last six starts against the Twins. He gave up two runs and four hits over seven innings in the most recent matchup, a 3-2 win at Target Field on May 17.
Buchholz, though, heads into this start after struggling in an 8-0 road loss to Texas on Friday. He allowed six runs and 10 hits over 4 1-3 innings after posting a 2.70 ERA in back-to-back wins.
Joe Mauer, batting .344 in his last 16 games against Boston, is 5 for 13 with three doubles in his career versus Buchholz. Kurt Suzuki is 6 for 12.
Napoli is 5 for 9 with two home runs against Hughes and Mike Carp is 5 for 10.