The two-time Cy Young winner Santana (6-2) struck out eight batters and allowed two earned runs in seven innings to help the Mets win their first inter-league matchup of the year.
New York made three errors to put Santana in a bit of trouble, but the left-hander worked his way out of tricky situations in the first and sixth innings.
"We cannot afford to make a lot mistakes, that's for sure," Santana told reporters. "It seems like every time I'm out there, we cannot get things done. But at the same time, they backed it up."
Japan's Matsuzaka, pitching for the first time since April 15 when he went out with arm fatigue, had a light outing of 80 pitches over five innings. The loss dropped his record for the season to 0-2.
Matsuzaka has allowed at least four runs in all three of his starts this season.
New York broke open a 1-1 tie with three RBI singles in the fourth inning from David Wright, Omir Santos and Ramon Martinez.
Martinez also made two errors, including one in the fourth that helped Jason Varitek reach base and two runners score to make it 4-3.
Bobby Parnell and Francisco Rodriguez pitched the final two innings to nail down the game and allow New York (22-19) to snap its four-game losing streak.
Boston (25-17), second in the American League East, had its three-game winning streak broken up.
First baseman Kevin Youkilis and Santana had a small altercation in the fifth inning when he was hit by a pitch. Youkilis stared down Santana, who yelled at him.
"He wanted me to go down to first base and not joke around, I guess," Youkilis said. "But I wasn't mad. I've been hit so many times. You joke around one time, I guess, and pitchers don't like it."
