Washburn pitched well for most of the game and struck out four in the first two innings, retiring the first three batters he's faced for the fourth time this season.
But he loaded the bases with one out in the third, and Sheffield, a .412 career hitter against Washburn, capitalized on a changeup that he hung over the plate.
The pitch was blasted into the Mariners bullpen in left field and gave Jeremy Bonderman all he needed to keep Seattle down for good.
"[Sheffield is] one of the greatest hitters ever, I think, in my opinion, and if you make a mistake to a guy like him, he's going to hurt you," Washburn said. "One through nine, they've got guys that will hurt you, and I don't think right-handers go into a game feeling really comfortable against them."
Washburn finished the game after six innings, allowing five runs (four earned) on seven hits while striking out seven.
"I thought we made Washburn work hard," said Tigers manager Jim Leyland. "We started out the game really hot. [Washburn] is hard to pick up."
Bonderman allowed three runs in seven innings, earning his 10th win of the season, and has the highest winning percentage in the American League.
"He's not 10-1 by mistake," said Mariners manager John McLaren. "He's a good pitcher. He's got a lot going for him, and when you battle these guys, that's quite a pitching staff they have over there."
The day started on a high note for the Mariners, who signed All-Star center fielder Ichiro Suzuki to a five-year, $90 million contract earlier in the day. Not much surfaced in the game for the Seattle's star, though, as he was just 1-for-4 with two strikeouts.
He wasn't the only Mariners batter having trouble with production, though.
Bonderman, a native of Kennewick, Wash., sent the Mariners down in order three times and never faced more than five hitters in a single inning.
Washburn worked his way out of a bases-loaded jam in the fifth inning. After intentionally walking Sheffield to load the bases with one out, he induced Magglio Ordonez into a double play, keeping the Mariners within striking distance.
But the damage had already been done, and they couldn't get that third-inning pitch back, no matter how desperately they wanted it.
"One bad pitch and one of the best RBI guys in the league in the last 10 years hit one out," McLaren said. "That's basically what the game was."
The teams have now split the first two games of the four-game series, and while the Tigers maintained their half-game lead over the Indians in the AL Central, Cleveland's win knocked the Mariners two games out of the Wild Card race.
It wasn't all bad for the Mariners, though, who managed some run production against one of Detroit's many aces.
Jose Guillen put the Mariners up, 1-0, in the second inning with a leadoff home run, his second career homer off of Bonderman. Beltre also homered for Seattle, another leadoff home run, this one in the seventh.
Seattle's bats will continue to be challenged over the weekend with pitchers Kenny Rogers and Justin Verlander set to take the mound. It may be a scary combination, but it's a test the Mariners want to take.
"It's a big test," said first baseman Richie Sexson. "This is pretty much the same team that went to the World Series last year, so they have a great club over there."
And although the Mariners won Round 1, the Tigers rebounded to take the second game.
If Seattle is to be considered one of the elite teams in the league, McLaren knows they need to expose any mishap the Tigers commit.
"Good teams capitalize on mistakes, and we did last night, and they did tonight," he said. "It's two very good ballclubs, and it was two very good ballgames."