"If I'm out there missing pitches, both the catcher and hitter are having trouble with it, then it's a good sign," Boston catcher Kevin Cash said. "When the hitters are not having awkward swings that's not a good sign."
Wakefield (4-4) allowed two runs and five hits, just three of them beyond 30 feet. He struck out six and walked two.
It looked like a backyard game of catch, with Wakefield getting the ball and pitching quickly. One knuckler to Kenji Johjima in the second inning was clocked at 56 mph.
"I've always been the type that likes to keep the game going," Wakefield said. "I slow the game and make adjustments. Obviously, I didn't need to today, so I just wanted to get the ball and keep throwing."
Boston rebounded from Friday's 8-0 loss to Seattle for its seventh victory in nine games; and 16th of 18 at Fenway Park.
"He's extremely tough on us," Seattle manager John McLaren said. "He's a tough pitcher to hit and he's a good competitor. I don't know what else to say."
Wakefield suffered 1-0 complete-game loss to the Mariners in Seattle on May 28 when Yuniesky Betancourt hit a homer.
"He had a really good one today," said designated hitter Jose Vidro, who was 0-for-3 against Wakefield. "I think we just got lucky when we got one off him [in Seattle]. He was better today, really good stuff."
Ramirez tied Eddie Murray for 23rd on the career list with a two-run drive over the Green Monster seats. J.D. Drew homered, tripled and singled.
One thing did go wrong for the Red Sox, Kevin Youkilis dropped a throw in the ninth, ending his major league-record 238-game errorless streak at first. He started the game at third, but moved over in the eighth.
"The ball was on me when I spun [to cover first], that was it," Youkilis said. "It's no big deal."
But it has been a tough few days for Youkilis, who was involved in a dugout dustup with Ramirez on Thursday.
Ichiro Suzuki had three singles, one a dribbler halfway to the mound and another a bunt, for Seattle.
The game featured knuckleballers pitching for both teams. R.A. Dickey worked in relief for the Mariners.
Miguel Batista (3-7) gave up five runs -- four earned -- and four hits in 4 1/3 innings for Seattle. He's allowed 10 runs and 11 hits in the opening inning of his last seven starts.
Drew homered off Dickey in the sixth, and singled home a run in the eighth.
Mike Lowell and Youkilis had two-run doubles in a five-run eighth.
Ramirez, who missed Friday's game with a sore right hamstring, gave Boston a 2-0 lead in the first with his sixth homer in 12 games after Drew's liner got past center fielder Suzuki for a triple.
The Mariners had some awkward swings in the first two innings, with Suzuki's roller in front of the plate the only hit. Wakefield fanned four of the first seven batters he faced.
Raul Ibanez tied it with a two-run double off Wakefield in the third.
Wakefield last faced a fellow knuckleballer when Charlie Haeger of the White Sox worked against him in Fenway Park last July 22. ... Boston manager Terry Francona said CF Jacoby Ellsbury, who left Thursday's game with a sprained right wrist, could be back Tuesday. ... Francona tied Jimy Williams for sixth in club history with his 414th win. ... Youkilis limped slightly to the dugout after trying avoid 1B Richie Sexson's tag of a wide throw, but stayed in the game. ... Mariners RHP Mark Lowe turned 25. ... Seattle fell to an AL-worst 8-21 on the road. ... Wakefield was winless in his last five starts, going 0-3.