Pedroia's three-run blast in the fourth broke a 1-1 tie, and the Red Sox led for the rest of the day.
J.D. Drew, who had supplanted David Ortiz in the three hole on Tuesday, batted second for the first time in his three seasons with the Red Sox, delivering an RBI double.
Kevin Youkilis batted third for the third time this season and ripped two homers. Jason Bay served as the cleanup man, unloading for his 15th homer of the season. Mike Lowell batted fifth and contributed a pair of doubles.
Ortiz, still in the throes of an epic slump, remained in the six spot for the sixth straight game. Though he went 1-for-5, Big Papi had a double off the wall to jump-start the three-run fourth.
"Again, we set out our lineup, and then I think you let guys play and see how it goes," said Francona. "We're getting to the point where we're  games into the season, and I think the numbers start meaning something. It's not just a week or two. We need to have our on-base guys for the guys in the middle of the order. It's important. When everybody is hitting on all cylinders, that can maybe not be noticed. But when we're not, it becomes a little more noticeable."
The Red Sox had scored just 12 runs in their previous five games entering Sunday.
Francona wasn't sure which lineup he will have out there for Tuesday night's game in Detroit, but it could be different with right-hander Rick Porcello going for the Tigers. Boston faced lefty starter Ricky Romero in this one.
Though Ellsbury has been swinging the bat well of late, he has a .274 slugging percentage against lefties this season. Whether his move to the bottom portion lineup is temporary or not, Ellsbury has a positive outlook.
"Being a young player, I'm not trying to look into it," Ellsbury said. "Just go out there and play. Things will take care of [themselves]. Hopefully, it helps the team. That's the most important thing."
All of Ellsbury's 47 previous starts this season had been at leadoff. Ellsbury batted eighth five times in 2008.
As for Pedroia, the leadoff spot was nothing new for him. That is where he batted for most of 2007, when he was the American League's Rookie of the Year. During his Most Valuable Player season of 2008, Pedroia started 17 games at leadoff.
Then there is Drew, whose versatility has led his managers to hit him all over the lineup throughout the years.
Though this was his first time batting second in Boston, Drew hit there twice for the Dodgers in 2006, and started 46 games in that slot for the 2003 St. Louis Cardinals.
"I've hit all over the place," Drew said. "I looked up and saw where I was at. It was pretty close to the three-hole. I wasn't really worried about it. Nothing changes. Same thing, same approach. Just another spot."
The other notable thing about Sunday's lineup is that Nick Green was at short for the second day in a row with Julio Lugo, who has played spotty defense since returning from the disabled list on April 27, again on the bench.
"You know what, just thinking on turf with [Jon] Lester, I think we're going to try to maximize his range," Francona said. "I wish I had a crystal ball and could see what would happen today, but I just think, on this turf, with Lester throwing that cutter to righties, I think it maybe gives us a little better chance."
Green robbed Aaron Hill of a hit in the third, ranging deep into the hole and throwing to Pedroia for the force.
All in all, it was a rewarding Sunday for the Red Sox, who are 3-4 on this three-city journey with three games to go.
"It was a nice way to end the series. We hadn't been swinging the bats all that well," said Lowell. "Home runs and doubles, I think that added a little exclamation point, and it provided instant offense. It was nice. Instead of banging out 15 hits and scoring five runs, it's much better to have eight runs and 11 hits. That's pretty solid."