Sampdoria took advantage of a mistake by Inter teenage star Davide Santon to break open a tight affair on Giampaolo Pazzini's goal in the 72nd minute.
Santon slipped, allowing Daniele Mannini to take a loose ball and cross for Pazzini to score the winner.
"Santon made a mistake," said Inter coach Jose Mourinho, "but any player can make a mistake. Never in my career have I had a player who hasn't made a mistake."
Sampdoria handed Inter its first loss of the season and took first place over Juventus, which was held to a 1-1 tie by Bologna.
"We did the same as we did for all five matches so far," said Pazzini. "We lost to Fiorentina in midweek, but tonight we did as we always do, worked hard and had a great game."