The 1-0 victory at Luigi Ferraris Stadium ended a 10-match winless streak against the Italians, an enormous achievement for the Americans even though it came only in a friendly match.
Italy had enjoyed a 7-0-3 record against the United States and suffered its first loss in Genoa in almost 90 years. Italy is ranked eighth in the world and the Americans are No. 31.
The Italians had most of the chances, including one by Alessandro Matri in the game's opening minutes that was stopped by Tim Howard.
Dempsey scored inside the left post after taking a pass across the penalty area from Jozy Altidore.
This was the 10th international appearance for the United States since Jurgen Klinsmann took over as the national coach and the Americans have won five of those contests. The United States will next play a friendly against Scotland May 26.