Zambrano gave up one hit over eight innings, and Aramis Ramirez drove in two runs, including one on a tie-breaking homer in the sixth, to lift the Cubs to a 5-1 victory over the Cincinnati Reds.
"He was the ace we know we have," catcher Geovany Soto said of Zambrano (10-3), who struck out five.
Zambrano did not walk a batter, and the only blemish was Adam Dunn's solo homer with one out in the Reds second, his 23rd.
"Tonight, he was really, really good," Dunn said of Zambrano. "The pitch I hit was probably the only mistake he made the entire game. That was probably the best I've seen him in a long time."
"That was a bad pitch," Zambrano said of the pitch to Dunn. "It was supposed to be down, and it stayed at eye level. He's a good hitter. After that, I said, 'Forget about it, just pitch your game, and just think about three or four more innings and pitch your game.' I knew our offense would come back and win the game for us."
This was Big Z's second start since coming off the disabled list, and the Cubs had preset his pitch count to 100-105. He was pulled after throwing 103.
"We let him hit," Cubs manager Lou Piniella said. "That appeased him a little."
And Zambrano came through, delivering a single with one out in the eighth. He's one hit shy of his total hits (20) in 2007, and batting .358.
"He always gives you 100 percent, he always gives you a quality outing," Soto said of Zambrano. "He's a really, really good competitor."
The only other Reds baserunner off Zambrano was Jeff Keppinger, who was safe on an error by Ramirez with one out in the first, but he was snuffed out on a double play when he was caught stealing as Ken Griffey Jr. struck out swinging. Shortstop Ryan Theriot robbed Jay Bruce of a potential base hit when he snared the ball behind second base, spun around, and threw in time to first to end the Reds sixth.
"It's hard to win with one hit," Reds manager Dusty Baker said. "That's Zambrano. He threw a great game tonight."
As Zambrano came off the field after a 1-2-3 Reds eighth, the sellout crowd of 41,605 rose to its feet to cheer. This was his last start before the All-Star break, and he is the second Cubs pitcher to reach 10 wins, joining Ryan Dempster (10-3). Ted Lilly (9-5) will try to become the third on Thursday for the Cubs, who have a 4 1/2-game lead.
"He pitched well, didn't he?" Piniella said of Zambrano. "He had good movement on his fastball, he used his split-finger effectively, mixed in his slider. It was good pitching, really good pitching."
Zambrano was three outs shy of posting a low-hit personal best. He has thrown a pair of two-hitters, most recently June 16, 2007, against San Diego, which also was his last complete game.
"I was thinking about that," Zambrano said about going the distance. "It's been a long time since I pitched a complete game. But not in this situation. I came off the DL one start ago, and it's too soon. Hopefully, in the second half of the season, I will have a chance to throw a complete game."
The Cubs tied the game in the second when Soto, another All-Star, doubled and scored one out later on Keppinger's fielding error. Ramirez, who also will go to the All-Star Game next week along with Soto, Zambrano and four other Cubs, led off the sixth with his 16th homer.
Reed Johnson singled to open the Chicago seventh, and advanced on Zambrano's sacrifice, although the pitcher appeared to be safe on the play. One out later, Johnson scored on Kosuke Fukudome's double, and he tallied on Derrek Lee's single to chase Johnny Cueto (7-9). Ramirez, who seems to be over his 0-for-28 skid, greeted David Weathers with an RBI double.
"Everybody is going to go through it," Ramirez said of his funk. "The only guy I've never seen struggle is Albert Pujols. Everybody goes through a tough stretch like that, but I feel pretty good right now."
The Reds did threaten in the ninth, loading the bases against Carlos Marmol, who survived a collision at first base with Paul Bako. Marmol had some marks on his right ankle, but stayed in the game.
"It scared me," Marmol said. "But no problem."
Kerry Wood, who has been bothered by a blister, got the final out for his 23rd save. New acquisitions Rich Harden and Chad Gaudin, both in uniform on Wednesday, had to like what they saw, both pitching-wise and offense-wise.
"We try to consider ourselves a pitching-oriented team," Piniella said. "We give the ball to our starters, watch the pitch counts carefully, and we're fortunate that we have some people in the bullpen who can get the job done. It's a tribute to our starters and a tribute to our bullpen that they hold onto the lead."
Carrie Muskat is a reporter for MLB.com. This story was not subject to the approval of Major League Baseball or its clubs.