Halladay is now 8-1 in his career against the Twins, who got to him with late runs. Orlando Cabrera tied it with his sixth homer to lead off the sixth, which ended a string of 222 consecutive at-bats without a home run by Minnesota.
Justin Morneau of New Westminster, B.C., hit his 30th home run on the first pitch to him with two out in the eighth.
Michael Cuddyer hit an 0-2 pitch for a two-run, pinch-hit double with one out in the ninth to put the game away for Carl Pavano (12-11), who allowed six hits in 7 1/3 innings.
Joe Nathan pitched the ninth for his 38th save.
The only thing Halladay (14-9) got from the effort was his seventh complete game of the season.
Despite the result, Halladay pitched well enough to win many games, allowing nine hits, one walk and striking out nine. But he took no solace in those stats.
"I'm not happy, it's frustrating," Halladay said. "You learn from it and move on. The one that obviously hurts is Cuddyer's two-strike pitch. I left it up a little bit.
"There were times when they were aggressive all game and we used it to our advantage. It works both ways if you make good pitches."
Halladay was particularly upset with Cabrera's homer on a 1-0 pitch that led off the sixth. It came after the Blue Jays took a 1-0 lead in the bottom of the fifth on Travis Snider's double.
"[The home run pitches] were bad pitches," Halladay said. "Especially the one to Cabrera. It was a lot middle. The one to Morneau wasn't as bad but he's a good hitter, a ball up, you pay for it."
It is the third time in his career that Morneau has hit at least 30 home runs in a season. Among Twins, only Harmon Killebrew has had more 30-homer seasons and he had eight, one reason he's in the Hall of Fame.
It was another start in which Halladay did not receive much run support. A few runs, especially early, can be huge in the hands of a pitcher like Halladay.
"He probably doesn't like what he did, but once again we should have scored three or four runs and we didn't do it," Blue Jays manager Cito Gaston said. "You score those runs and it's a different ballgame. He made a couple of mistakes, but overall he pitched great."
"We didn't get the job done offensively," Snider said, but
Halladay didn't want to hear about run support.
"Don't worry about that," he said. "That's not in my control. I have to worry about making pitches, that's what my job is. Win or lose, that's got to be a focus for a pitcher. You just can't get caught up in that, you have to stick with your approach, that's all you can do. I didn't do it later."
Asked what frustrated him most about the game, he said, "Losing, that's it. You win those games, 6-4, you're happy. I know I made mistakes that cost me and that bothers me. Any time you're not winning games it's frustrating."
Gaston was asked about the small crowd.
"In order to get back to where we're going, we need our fans out here, we need their support," Gaston said. "Hopefully they will realize that and come out and support us. I still think the guys are going out there and trying as hard as they can. But you can only do so much. They're trying, that's all you can ask them to do is try."
Halladay took a career 2.77 ERA in 12 games (10 starts) against the Twins into Wednesday's game. He also had a save early in his career against Minnesota. Halladay defeated the Twins this season on April 16 at the Metrodome.
The Blue Jays scored their only run in the fifth. Snider doubled after Edwin Encarnacion's leadoff triple. The relay throw hit Encarnacion as he slid into third. John McDonald, who hit the game-winning, three-run homer on Tuesday, grounded out to move Snider to third. Marco Scutaro walked, but Jose Bautista struck out and Adam Lind ended the inning by forcing Scutaro at second.
The Twins gave themselves a cushion in the ninth when Delmon Young led off with a double and Alexi Casilla ran for him. Brian Buscher singled and took second on the throw that kept Casilla at third. Mike Redmond struck out, but Cuddyer did not miss on the 0-2 curveball.
Now the Blue Jays must win on Thursday to gain a split of the four-game series.