Youkilis was activated prior to Tuesday night's game against the Orioles and inserted into the lineup at first base instead of the hot corner. First baseman Adrian Gonzalez moved to right field, where he played two games last weekend in Interleague games at Philadelphia.
Meanwhile, top prospect Will Middlebrooks remained on the roster and got the start at third base.
Youkilis, who batted fifth and struck out in his first at-bat, launched a solo homer in the fourth inning.
Outfielders Cody Ross (fractured left navicular bone) and Ryan Sweeney (concussion) were both placed on the disabled list prior to Tuesday's game.
In addition, the contract of veteran outfielder Scott Podsednik was purchased from Triple-A Pawtucket and Daisuke Matsuzaka was moved to the 60-day disabled list, though he's still eligible to return on June 3.
These are complicated times for general manager Ben Cherington and manager Bobby Valentine, as they try to get creative given all the injuries.
Under ordinary circumstances, Middlebrooks might have been sent back to Pawtucket, despite how well he performed while Youkilis was absent.
"It's a compounded situation," said Valentine. "It's just not that Will's hitting well; there's this void in the outfield. And it seems like the situation presented what at least today's solution is about."
It remains to be seen how much Youkilis and Gonzalez will play first and right.
"That's for them to decide," said Youkilis. "We definitely have a good team with all of us in the lineup. It stinks for Cody to be out. Hopefully he gets healthy as soon as possible and returns to help this team."
Tuesday marked the first time Gonzalez played right field for the Red Sox in a non-Interleague game.
Gonzalez took offense to the notion that asking him to play right field could be asking too much of him physically.
"I don't see how it affects me. It changes position -- that's about it," Gonzalez said. "Why would I worry about my legs? I told Bobby Valentine I played three seasons where I played 160 games and then went and played winter ball. I'll be fine. Have you seen me running fast out there? How is it going to affect my legs?"
Valentine said he isn't sure how often he will ask Gonzalez to play the outfield. Don't look for Gonzalez to play much outfield -- if at all -- at Fenway Park.
"Even in a small outfield, we'll have to appraise that situation as we see it more. I would say that probably less is better than more," Valentine said. "I don't think he'll mess up anything. They're just might be a few that he doesn't get to. If it comes to the point that there's just outs that were given out, then we'll probably scratch the idea.
"Any outfielder, if you don't get to the baseball, it's a hit. It will become a little subjective after a while. If it's obvious the ball should be caught and it's not caught, we'll have a different appraisal."
As for Youkilis, switching corners to him is the equivalent to riding a bike. Youkilis was Boston's full-time first baseman from 2006-10.
"I'm excited to play and hopefully we go out there and win a series," Youkilis said. "Just be healthy and play. That's what I want to do."
Youkilis, who was on the disabled list with a lower back strain, last played for the Red Sox on April 28. He entered the night hitting .219 with two homers and nine RBIs. Youkilis hit .364 in a four-game rehab assignment for Triple-A Pawtucket.
"I've been swinging pretty good," Youkilis said. "Just trying to get back in the swing [of things]. I felt good yesterday."