Lowrie, who has had issues with a bum left shoulder, went 0-for-5 in Saturday's 16-4 rout in Toronto. He was the only starter without a hit and a run scored, running his hitless streak to 11 at-bats overall.
Lowrie's return comes against Rays right-hander Jeremy Hellickson. Their only encounter resulted in an RBI double for Lowrie, who hits seventh Wednesday.
Few Red Sox starters have much experience against the 24-year-old Hellickson. Collectively, they are 6-for-19 (.316) with three doubles, one triple and four walks.
That triple came off the bat of Adrian Gonzalez, who enters this one leading the majors with a .347 average, 60 RBIs and 22 doubles. Gonzalez had a career-high nine-game RBI streak snapped in Tuesday's series opener, but he did have three hits and is batting .423 (22-for-52) in his last 13 games.
Jason Varitek returns to the lineup with Josh Beckett on the mound. Varitek is batting .317 (19-for-60) over his last 17 starts behind the plate.
Here is the complete Boston batting order against Hellickson:
Jacoby Ellsbury, CF
Dustin Pedroia, 2B
Adrian Gonzalez, 1B
Kevin Youkilis, 3B
David Ortiz, DH
Carl Crawford, LF
Jed Lowrie, SS
J.D. Drew, RF
Jason Varitek, C