The four-time All-Star closer was drafted by the Sox in the fourth round of the 2003 First-Year Player Draft and racked up a club-record 219 saves while being an anchor in Boston's bullpen.
"I think it's obviously going to be a little different because of his history here and how long he's been here," Red Sox catcher Jarrod Saltalamacchia said. "It will be a little different, but I think once game time comes down, it's still a game and you kind of forget about it."
Yet before Papelbon has the chance to take the hill, Daniel Bard and Cole Hamels will square off at Citizens Bank Park.
Hamels hasn't lost a game for the Phillies since his first start of the season on April 9, a span of six starts. In that time, he's gone 5-0 with a 1.93 ERA, walking nine and striking out 40 over 42 innings.
On Sunday against the Padres, Hamels surrendered just one run on five hits in seven innings of work. He also struck out five to improve to 5-1 on the season with a 2.28 ERA.
Meanwhile, Bard comes into Friday's contest after a win and quality start against the Indians on Sunday.
While the Red Sox right-hander wasn't pleased with his fastball command during the game, he allowed only one run on six hits in six innings of work.
"It forced me to use the changeup and use the breaking ball," Bard said. "That's what kept me in the game and kept them off-balance just enough."
Red Sox: Ortiz to play first base
Manager Bobby Valentine said on Thursday that he plans on having at least one game against the Phillies in which designated hitter David Ortiz will play first and Adrian Gonzalez will move to right field.
"I'm fine," Ortiz said. "No fear. Never from Papi. Wish me good luck."
The Red Sox were encouraged after hearing of Kevin Youkilis' 1-for-2 performance with Triple-A Pawtucket on Wednesday.
"He hit a 94-mph fastball. He was real aggressive at the plate," Valentine said. "He got all of his work. He battled a walk. It sounds like he had a good night."
Youkilis took Thursday off and will play third base for Pawtucket on Friday after serving as the designated hitter in his first game.
Phillies: Utley clears another hurdle
While Chase Utley sounded upbeat on Thursday at Wrigley Field, he was cautious in saying he'd be back in the Phillies' lineup during the next few weeks.
However, the second baseman said he took a positive step on Wednesday, when he fielded ground balls during batting practice for the first time since rejoining the team on May 5. Utley, who is on the disabled list with chondromalacia in his left knee, said he still feels some discomfort in the knee, but it has improved.
"Over the past year or so, I know the pain threshold I can play at," he said. "And right now, I'm in the good zone. ... There's a little discomfort, but that's a part of the whole process. Last year, when I started taking ground balls, it was a little uncomfortable as well, but the more I did it, the better I became at it."
Bard has a 3.00 ERA over the first five innings of his starts and a 10.29 ERA thereafter.
In four career starts against the Red Sox, Hamels is 3-0 with a 1.44 ERA.