Desmond's shot off Henry Sosa (2-4) in the third inning tied the game 2-2. Ankiel and Zimmerman then put the Nats ahead with their homers and Washington went on to take the rubber match of a three-game series.
Desmond finished 3-for-5 with two RBI and Zimmerman added a run-scoring single for the victors.
Stephen Strasburg made his second start of the season and went three innings, charged with one run on three hits with four strikeouts, while Tom Gorzelanny (3-6) earned the win for pitching three scoreless innings.
Carlos Lee got the only RBI for the Astros.