The 2008 American League MVP and four-time All Star went 0-for-4 with a walk and scored in Boston's 8-6 victory against the Atlanta Braves on Saturday.
He received a standing ovation when he came up with the bases loaded and two outs in the first. He flied out to right to end the inning.
"It was great to be back, a great win for us, and it was exciting," he said. "I'll never forget that first at-bat. That was pretty cool."
The 34-year-old Pedroia admitted to some nervousness in the clubhouse before batting practice.
"Yeah, it's been a long time, a lot of work put into to get to this point," he said. "So, yeah, I'll be a little nervous."
Pedroia had cartilage-restoration surgery on his left knee seven months ago. He was not in Boston's Opening Day lineup for the first time since 2007.
He batted sixth in his return to the Red Sox (36-16).
"I don't want to break up the top two," manager Alex Cora said. "I'm very comfortable with them the way they're getting on base.
"I think that's a good spot for him to have traffic in front of him."