Griffey's two-run shot off John Snyder (4-2) tied the game at 2 in the fourth inning and gave baseball's four leading sluggers a home run sweep for the day.
Mark McGwire hit his 53rd homer for St. Louis, Sammy Sosa hit his 50th and 51st for the Chicago Cubs and Greg Vaughn hit his 42nd for San Diego.
Griffey had not homered since Aug. 15 on the road against the White Sox.
"I'm on a cut-throat pace,"deadpanned Griffey after hitting just his second home run of August. He has two in his last 89 at-bats.
But that's still as many as Seattle rookie Shane Monahan has in his career, the second of which came in the fifth inning to provide the Mariners with the go-ahead run.
"The difference is I have two and they have 50," said Monahan when asked if he felt like he belonged in the same list as McGwire or Sosa. "They're unbelievable aren't they? I can't even fathom it. Fifty-three in my career would be fantastic."
Both of Monahan's homer have turned into game-winners.
"I guess the situation is lucky," he said. "I wasn't looking to hit one there. I was looking to hit one in the gap. I was thinking three (bases) and bring up Joey (Cora)."
Snyder lost despite a three-hitter. Chicago lost its season-high fifth straight game.
The Mariners have beaten the White Sox in the first three games of the four-game series by a combined three runs. Seattle had only four one-run victories coming into the series and still are on pace to break the 1985 Texas Rangers' 162-game record low of 11 one-run victories.
"You would think we would be doing a lot better," said Chicago manager Jerry Manuel. "The three parks we've been playing in are hitter-friendly, but we have just gone into the tank. It is hard to describe or explain."
Paul Spoljaric (4-2) won for the first time in three starts this season.
"Once we traded Randy Johnson, it opened up a spot for him and he's done well," said Mariners manager Lou Piniella. "He's more relaxed, he has more tempo, he's throwing the ball well."
Spoljaric went seven innings, giving up three hits and two runs
one unearned with no walks and six strikeouts. He threw 100 pitches in his longest career outing.
"I really enjoy it," he said of his role as a starter. "I feel like I have more control of the game. In relief, you come in into some situations that aren't always comfortable."
Bobby Ayala pitched a perfect eighth for Seattle. Jose Paniagua worked the ninth for his first major league save.
The Marines managed only three hits against Snyder, who took a hard-luck loss in his first career complete game.
"Monahan's was a good pitch but to the wrong guy," Snyder said, "and Griffey took advantage of a pitch he could drive. He probably should have hit it through the stadium. He got it pretty good."
Chicago took a 2-0 lead in the third on a solo homer from Wil Cordero, his 11th, and an RBI single by Mike Caruso.
Seattle third baseman Russ Davis had two more errors, giving him three in two games and a major league-leading 33 for the season.
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