In his second start since coming off the disabled list with a right shoulder strain, Zambrano (10-3) walked none and struck out five while throwing 103 pitches in a dominating performance.
But things got shaky for the Cubs after Zambrano left the game.
Carlos Marmol relieved to start the ninth and gave up a two-out single to Jay Bruce that went off first baseman Derrek Lee's glove, then walked Jeff Keppinger and Ken Griffey Jr. to load the bases.
Kerry Wood relieved and got Brandon Phillips to foul out to first to earn his 23rd save in 28 chances.
Other than Dunn's 23rd homer, the only Reds' baserunner against Zambrano was Keppinger, who reached on shortstop Aramis Ramirez's one-out error in the first, but he was thrown out trying to steal second as Griffey struck out.
Ramirez hit Johnny Cueto's first pitch in the bottom of the sixth into the bleachers in left center for his 16th homer to break a 1-1 tie.
Cueto (7-9) gave up eight hits and five runs, four earned, in 6 2-3 innings. The Cubs added three runs with two outs in the seventh when Kosuke Fukudome hit an RBI double on a fly ball that went over Dunn's head near the wall in left and Lee delivered an RBI single that finished Cueto. Ramirez greeted reliever David Weathers with an RBI double.
The Cubs tied it in the second with an unearned run as Geovany Soto doubled and raced home when shortstop Keppinger mishandled Mark DeRosa's grounder for an error and the ball ended up in short left center.
Notes: Zambrano is 13-9 in his career against the Reds, including 3-0 this season. ... Marmol was limping after covering first base and beating Paul Bako to the bag in the ninth. ... The Cubs will not activate LHP Scott Eyre (groin) until after the All-Star break although he could make some minor league rehab appearances this week. Manager Lou Piniella said OF Alfonso Soriano will probably not be ready to play until the second series after the All-Star break and that a minor league rehab appearance would also help him. He's been on the DL since June 12 with a broken left hand.