Ramon Santiago and Magglio Ordonez each hit two-run homers for the Tigers, who won their seventh straight. Micah Hoffpauir led off the ninth with his seventh homer, but the Cubs now have lost four in a row.
"We hit the ball a little better, which is good," Lou Piniella said of his team, which was 1-for-6 with runners in scoring position Thursday after going 1-for-23 in the first two games. "Hopefully, it carries over into the weekend against the White Sox."
Ted Lilly (7-5) took the loss, setting season highs in runs (six) and hits (10) given up. He's 0-1 with two no-decisions in three starts against American League teams.
"I'm disappointed," Lilly said. "The whole objective is to find a way to win and I don't feel like I did my part."
The lefty said there were a couple times when he had the right pitch selection, but didn't execute a quality pitch. There also were instances when he second-guessed some of his pitches.
"It wasn't very good all around," Lilly said. "I made too many mistakes, period. I can't come up with one reason why. There's more than one to look at."
Derrek Lee went 0-for-4 to end his hitting streak at a personal best 21 games. Alfonso Soriano doubled to lead off the game and Ryan Theriot walked to set up Fox's home run, a 411-foot shot that cleared the visitor's bullpen.
The home run ball was in his locker after the game. It was going to his dad, who was waiting for the 26-year-old outside the clubhouse.
"It was really nice to get that first one out of the way," said Fox, who had 17 homers at Triple-A Iowa this season. "It almost feels like there's a weight lifted off my shoulders. I think that's why I ended up having a pretty good day. [Hitting that home run] allowed me to settle in and relax and get into a rhythm. I think that's one of the reasons I've been, I guess you can say, struggling at the plate, because I've been trying to get that first one."
Fox attended the University of Michigan and had plenty of friends and family in the crowd of 42,332 at Comerica Park. When he checked his phone, he had 13 text messages waiting for him.
He also singled in the fourth and doubled in the sixth. But he struck out in the ninth against Fernando Rodney, and missed a chance at the cycle.
"Honestly, with the stuff he was throwing, I was worried about making contact," Fox said. "I wasn't really worried about where it went to or anything like that. I know [the cycle] was on people's minds. I was doing what I needed to do to win a ballgame, and unfortunately, I had a poor at-bat there. I guess you can't get them all."
Fox has hit safely in four straight games, going 7-for-16, with seven RBIs. The Cubs have been trying to find a spot for him to get the offense going.
"Fox swings the bat," Piniella said. "He's going to have some not-so-pretty at-bats. The kid's got some bat speed and he's swinging it. I'm going to let him play whenever I can get him in there. It's refreshing to see somebody go up there and powder river the ball, it really is."
Santiago belted his fifth homer with two outs and one on in the Detroit third to make it 3-2. Kosuke Fukudome, who was 1-for-12 on the trip, gave the Cubs a 4-2 lead when he hit an RBI triple with two outs in the Chicago fourth.
But the Tigers came roaring back. Marcus Thames and Ryan Raburn hit back-to-back doubles in the fourth to close to 4-3, and one out later, the recently shorn Ordonez smashed his third homer, a two-run shot, off an 0-2 pitch from Lilly.
The Cubs did catch a break in the Detroit first when Miguel Cabrera's ball bounced off the right-field wall for a double. The Tigers didn't challenge umpire Tim McClelland's call, but replays showed the ball hit the top of the wall, and should've been ruled a home run.
Some of the Tigers players saw the replay in the clubhouse, but Detroit manager Jim Leyland didn't have time to contest it.
"When I went back, I didn't know what it hit," Cubs right fielder Micah Hoffpauir said. "[McClelland] asked me if it was out, and I said, to be honest, I don't know."
Despite the Cubs' struggles, they're only 3 1/2 games back in the National League Central.
"This division seems to be open for the taking," Fox said. "All we can do is come back tomorrow, try to give it the best we've got. When the dust finally settles, we'll see where we're at."