On 31 May 2007 he was announced as new Sampdoria coach. He served as Sampdoria boss for two seasons, overseeing a considerable improvement in results, thanks to the likes of the attacking duo of Antonio Cassano, who publicly praised Mazzarri's coaching abilities, and Giampaolo Pazzini. Sampdoria's 2007–08 campaign ended in an impressive sixth place, which ensured qualification for the UEFA Cup. Mazzarri's fortunes declined slightly in 2008–09, as the "blucerchiati" ended their campaign in 13th place; despite this, he managed to guide his team into the Coppa Italia Final, notably defeating champions Inter 3–1 on aggregate in the semi-finals, before losing on penalties to Lazio in the final. Mazzarri left Sampdoria by mutual consent at the end of the 2008–09 season.