McLouth clubbed a 1-0 pitch from Yankees reliever Jose Veras into the right-field stands, knocking in Jack Wilson and putting Pittsburgh on top. It was McLouth's 18th home run of the season.
"It was a bad pitch," Veras explained. "I tried to go outside and the pitch moved inside to his hands, and he's got quick hands and he hit the ball. It was a bad pitch, and he just hit it."
The Yankees had their four-game winning streak snapped in the makeup game of a June 26 rainout.
Yankees starter Mike Mussina tossed six innings and allowed two runs on nine hits for a no-decision.
Yankees manager Joe Girardi felt Mussina deserved a better fate.
"There's been some games where we've had an opportunity to win, and Mussina's pitched great in the first half," Girardi said. "I'm looking forward to the second half and him pitching the same way."
"No, I don't feel unlucky," Mussina said. "I don't. We've played well in these games, and sometimes it's tough to get enough runs to win them. We haven't been scoring a ton of runs lately, and every one of them is important. Today, I didn't have my best stuff, I think I got some breaks. I think I got some line drives at people, but I spread the hits around enough and didn't walk anybody and I got the outs when I needed them.
"Two runs in six innings isn't bad. It could have been a little better, and it could have been a lot worse."
Veras had allowed only one earned run in his past 17 1/3 innings before surrendering the McLouth blast. He was tagged with the loss, falling to 2-1.
"It's not deflating," Girardi explained. "Jose Veras has been so great for us. None of our relievers, positional players or pitchers are going to be perfect. McLouth jumped on a fastball and he hit it well, and obviously, he's been hitting well for them all year, and they beat us."
Pirates starter Paul Maholm went eight frames and surrendered two runs on seven hits to notch the win and move to 6-5 on the season.
"I thought his breaking stuff was outstanding," Girardi said of Maholm. "His curveball, his slider -- he had great location and he located his fastball as well. He's probably been their most consistent starter and he showed why tonight."
Yankees right fielder Bobby Abreu tipped his cap to Maholm.
"Today, he was really good," Abreu offered. "He was trying to throw the ball in and out, and it worked for him.
The Pirates jumped out to a 1-0 lead in the bottom of the third inning. Wilson led off with double and scampered home on an RBI single by Freddy Sanchez.
Pittsburgh nicked Mussina again in the fifth inning. McLouth, who reached base on a fielder's choice, stole second base and advanced to third on a throwing error by Yankees catcher Jose Molina. McLouth scored on a sacrifice fly by Sanchez, upping the Bucs lead to 2-0.
The Yankees broke through against Maholm in the seventh inning. With two outs, Justin Christian and pinch-hitter Wilson Betemit stroked back-to-back singles. Derek Jeter was hit by a pitch to load the bases. Then, Abreu delivered a two-run single to tie the game at 2.
Pirates lefty Damaso Marte pitched a scoreless ninth inning to notch his fourth save.
The Yankees ended Interleague Play with a 10-8 mark. They open a three-game series in Toronto on Friday.
"You have to score one more run than them," Girardi said. "Maholm was very tough on us tonight, and we're facing a lot of good pitchers, and obviously, our division has outstanding starters. We're going to see another tough pitcher on Friday. So we've got our work cut out for us, and we've got to put this one behind you and get ready for Roy Halladay and find a way to win that game."
George Von Benko is a contributor to MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.