Boston made it interesting in the ninth, scoring two runs off Ryan Dempster, who held on for his eighth save.
"These guys aren't going to quit -- they're not the World champions for nothing," Cubs manager Dusty Baker said.
The Cubs, who have collected 32 hits in the two games so far, overcame a 4-0 deficit to tie the game. With one out in the sixth, Walker singled and reached third on Hollandsworth's double. Walker then scored on Henry Blanco's sacrifice fly. Walker's best at-bat may have been in the eighth when he grounded out to advance a runner and set up an RBI double by Aramis Ramirez and a RBI single by Hollandsworth.
This isn't a revenge series for Walker, who played for the Red Sox in 2003. It has been a chance for him to find his hitting stroke.
"With repetition of at-bats comes an educated guess of what pitches are coming," Walker said. "I had a great idea today. Those guys over there know me very well, too. That's what makes this a challenge.
"[Red Sox catcher Jason] Varitek, he knows how I think," Walker said. "For example, when I hit a curveball to left field my first at-bat, he knows I eliminate that pitch and start looking for other pitches. So my next at-bat, first pitch, curveball. It makes it difficult."
At least it wasn't painful. Cubs starter Carlos Zambrano gave up four runs on five hits over five innings before he had to leave the game with a sprained left big toe injured when he slid into second base in the fifth. X-rays were negative, and he was not expected to miss his next start.
Todd Wellemeyer (2-1) picked up the win, pitching one inning in relief in front of 39,096 at Wrigley Field. There were a lot of "Let's Go Red Sox" chants during the game.
"All I heard was 'Let's go Cubs,'" Dempster said.
So where did all these Red Sox fans come from?
"I'm guessing Boston," Dempster said. "I talked to a friend of mine and he said 50,000 people flew in from Boston. I don't know if they all have tickets or they're just here to party. I don't think my grandfather was alive when we last played them, so it's big news on both ends as far as the fans go. It'll be the same thing when we go to Yankee Stadium [next weekend]. I'm sure there will be a lot of Chicago fans there."
They'll be eager to see the hot-hitting Cubs, who have won 12 of their last 15 games, and are 4-4 in Interleague Play this season. The Cubs started the day leading the National League in home runs, but didn't hit a single one.
"I thought it was just a matter of time before we meshed," Hollandsworth said of the offense.
The Red Sox had taken a 4-0 lead on Trot Nixon's three-run homer in the first and Bill Mueller's solo shot in the second, both off Zambrano.
The Cubs rallied, and rapped five straight hits off Wade Miller (2-2) to open the second, including RBI singles by Walker and Hollandsworth. Another run scored when Zambrano grounded into a double play to close to 4-3.
With one out in the Cubs fourth, Walker tripled and scored on Hollandsworth's groundout to tie the game. In his at-bat, Hollandsworth fouled a ball off his left knee and collapsed to the ground. He's already wearing a shin guard to protect his right leg from an errant foul ball.
"Guys usually foul it off and miss their legs," Hollandsworth said. "Mine don't. My legs are just a wreck. You might see me wearing two shin guards tomorrow."
As long as he keeps hitting, it'll be fine. Hollandsworth is batting .462 (12-for-26) in eight games this month, and got a charge from the fans.
"It was a playoff atmosphere, no doubt," he said. "You could sense it in the crowd -- they were sitting on every pitch in the fifth inning. That's playoff atmosphere."
"We've won two games in a row against the World champions," Walker said. "And I think we can be proud of ourselves for that for tonight, and we have to come out tomorrow and you have to play them again. Overall, we've done well against these guys."