Jason Kubel homered twice and drove in five runs for Minnesota, lighting up the shaking hands of the Twin Cities logo in center field with a solo shot off Vazquez in the sixth inning and a three-run blast off reliever Chad Gaudin in the seventh.
But long before Kubel took a curtain call, Vazquez was in trouble early, struggling to command his breaking pitches. Even the outs he recorded were of the loud variety, and it was a step back after Vazquez had encouraged the Yankees he was shaking off his slow start.
"As a pitcher, you just know that you're going to have some tough games like that," Vazquez said. "They seem like they're hitting every ball or a lot of balls hard. If they're outs, they're outs. If they're hits, they're hits. Sometimes they're going to drop out there."
The final line saw Vazquez charged with five runs on eight hits in a shaky 5 2/3 innings, accepting his fifth loss of the year. The defeat was the Yankees' first in Minnesota since Aug. 13, 2008, though they left town taking two of three in their first visit to Target Field.
"He made some pitches when he had to, to kind of keep it close," Yankees manager Joe Girardi said of Vazquez. "But obviously if you don't make pitches against this team, they can put a thumping on you, and that's what they did.
"We had some hits and at times we strung some hits together, but we weren't able to have the big inning. Some of the balls we hit hard were caught, but we couldn't get the big inning together."
Minnesota jumped out to a 3-0 lead after two innings, with Justin Morneau lifting a sacrifice fly, Kubel stroking an RBI double and Alexi Casilla hitting into a run-scoring double play.
Though Vazquez settled in, Orlando Hudson opened the fifth inning with a triple and scored on Jim Thome's sacrifice fly, and Kubel slugged a solo homer in the sixth -- his fourth -- snapping the Twins' homer drought of 349 plate appearances.
"I think even though we got the loss, I battled out there," said Vazquez, whose ERA went from 6.69 to 6.86. "My first few games early in the season, probably I wasn't battling as well as I did today. Really, the first couple innings for me were the two innings that hurt me the most, because I didn't make good pitches."
The rough start interrupted a string of three good appearances by Vazquez, including a seven-inning loss on May 12 at Detroit, a winning one-out relief appearance on May 17 against the Red Sox and six innings of scoreless, one-hit ball against the Mets on May 21.
Vazquez had to leave that last start due to a bruised right index finger, which he said he didn't even feel on Thursday. The problem was command, and as several hitters around the league have noticed, Vazquez needs to have his best touch to pitch without his old fastball.
"Obviously I think I've got to locate better," Vazquez said. "When you don't have your good fastball, you've got to locate better. And that's what I'm trying to do."
The Yankees were limited to two runs in seven innings by Nick Blackburn, with Robinson Cano driving in both after coming into the game 0-for-11 lifetime against Blackburn.
"I leave that in the past," said Cano, who has a 10-game hitting streak. "It's a new game, a different game. I just go up there and get a pitch that I can be able to drive and make a good swing."
Cano dropped a single into center field off Blackburn in the fifth that sent Brett Gardner home, then he knocked in Mark Teixeira -- who offered a positive with a 2-for-4 night -- with a sixth-inning double that scooted down the right-field line.
But those were the Yankees' only hits in seven chances with runners in scoring position. Some of it was bad luck, like Alex Rodriguez hitting into a first-inning double play, but Blackburn also got New York to pound his sinker into the ground with regularity.
"Those guys are dangerous," Blackburn said. "To go out there and face them over and over is never fun. I'm glad we're done with those guys, obviously. ... I think they have a pretty good idea of what I'm doing out there."
The Yankees didn't seem to be taking the loss exceptionally hard, as Girardi made a point to remind visitors to his office that they had posted two wins within the span of a few hours on Wednesday to win the series.
But Thursday offered reminders of two lingering problems for the flight home -- Vazquez's ineffectiveness and the issue of searching for big hits with runners in scoring position.
"This is baseball," Cano said. "We are not going to be perfect all the time. We're going to have some ups and downs, but we're going to put it together soon. We've got to be ready and keep it together as a team, and keep fighting."
Bryan Hoch is a reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.