Light-hitting Doug Mientkiewicz also connected and Derek Jeter passed Joe DiMaggio for fifth place on the franchise hits list to help the Yankees take two of three in the series and move within 9½ games of AL East-leading Boston.
"Right now, we don't have a choice. Every series becomes a mini playoff series," Alex Rodriguez said. "You lose this one, it would really hurt."
Matsui drove in three runs, while Jeter, Mientkiewicz and Johnny Damon had three hits apiece. New York roughed up Schilling (4-2) for 12 hits, the most he had allowed since yielding 13 on April 22, 2004, at Toronto.
"Most of the hits were mistakes and they hammered them," Schilling said. "My last 12 innings, I've given up 24 baserunners. It's not just the stretch, it's everything. I've got to pitch again in five days and I've got to figure it out in the next four."
Before the game, Yankees designated hitter Jason Giambi met with lawyers from the baseball commissioner's office to discuss his recent comments about steroids -- on the same day a report alleged he failed an amphetamines test within the last year.
New York manager Joe Torre said "we have no knowledge" of a positive test.
There also was news on oft-injured pitcher Carl Pavano, who is headed for reconstructive elbow surgery that will probably end his unproductive stint with the Yankees and make his contract a $40 million bust.
Plus, Roger Clemens made the second minor league start of his latest comeback Wednesday night, throwing 102 pitches over 5 1/3 innings for Double-A Trenton. If he feels ready, he could join New York's rotation next Monday or Tuesday in Toronto.
Even with everything going on around them, the Yankees looked sharp in every facet. Damon led off the first with a double and scored on Jeter's single. Matsui followed with his fourth homer, a two-run shot that made it 3-0.
"Letter high, middle of the plate. It was supposed to be down and away," Schilling said. "I was consistently inconsistent when I couldn't afford to be."
Jeter added another RBI single in the second, giving him 2,215 career hits to pass DiMaggio.
"It's special. I'd be lying to you if I said it wasn't, but it's not something I was thinking about," Jeter said. "It just comes with time and playing a lot of years, I guess."
Rodriguez lined a leadoff double in the third and scored on Jorge Posada's single. Mientkiewicz homered off the facade of the right-field upper deck in the fourth for a 6-0 lead.
It was a rare outburst of run support for Pettitte (3-3), who took a shutout into the sixth before giving up Mike Lowell's two-out RBI double. The left-hander allowed one run and nine hits with one walk, lowering his ERA to 2.66 and improving to 14-6 against Boston.
"He doesn't throw the ball as hard as he did at one time, but he does a lot of things and he has a lot of courage," Torre said.
New York (21-24) is 3-6 against the Red Sox this year. One night after managing only four hits, the Yankees matched a season high with 16 in one of their best all-around games of the season.
The Yankees, who lost their previous three series, won for the fifth time in 13 games overall. All three games in the series were decided by at least four runs.
"We won the series. That's what we need to concentrate on really, not worry about winning 15 in a row," Pettitte said. "It was a huge series, there's no doubt."
Schilling gave up six runs -- five earned -- in six innings during his first loss in nine starts since opening day at Kansas City. He was 2-0 with a 3.60 ERA in his previous four starts against the Yankees, lasting at least seven innings each time.
"He's giving up a lot of hits," Boston manager Terry Francona said. "There were just a couple of balls in the hole on a night when he needed a break. I'm not saying they were dribblers, because they weren't."
Jeter tripled leading off the seventh against Brendan Donnelly and scored his second run of the game on Matsui's single.
Mientkiewicz doubled with two outs in the eighth and scored on Damon's single.
After allowing a leadoff double in the ninth, Mariano Rivera struck out the next three batters.
- Clemens allowed three runs and six hits against Portland, a Red Sox affiliate. He walked four, struck out five and threw 64 strikes.
- Youkilis extended his hitting streak to a career-best 16 games with a second-inning double.
- Jeter pushed his hitting streak to 18 games.
- Torre earned his 1,100th victory with the Yankees.
- Attendance was exactly 55,000.
- The Yankees honored victims of the Virginia Tech tragedy by painting school logos along the baselines and wearing them on their caps.