Zambrano (6-4) gave up an unearned run and four singles to win his second consecutive start after going 0-2 in his previous six outings. He struck out four and walked four in a 113-pitch effort as the Cubs won for the fourth time in five games.
Washington fell to 0-2 under interim manager Jim Riggleman, who took over when Manny Acta was fired Monday. Nyjer Morgan had three hits for the Nationals, who have lost eight of nine to lower their major league-worst record to 26-63.
Aaron Heilman, Sean Marshall, Carlos Marmol and Kevin Gregg combined to pitch four innings of two-hit ball after Zambrano departed, with Gregg earning his 17th save in 20 opportunities. Aramis Ramirez homered for the Cubs.
Zambrano labored through a 40-pitch first inning and the right-hander's control problems put him in a 1-0 hole. The Nationals loaded the bases on a pair of walks and an error before Willie Harris walked with two out to force in a run.
Second baseman Mike Fontenot's sprawling, backhanded grab of Josh Bard's grounder up the middle, followed by a no-look flip to shortstop Ryan Theriot for an inning-ending forceout, prevented further damage.
Zambrano quickly atoned for his wildness, coming up with a big hit in the second. Milton Bradley drew a leadoff walk and Fontenot doubled with one out to put runners on second and third. After Koyie Hill grounded out, Zambrano doubled down the right-field line to give the Cubs a 2-1 lead.
Ramirez hit a two-out drive off Craig Stammen into the seats in left in the third. It was his fifth homer.
