On 8 January 2011, Sampdoria confirmed Macheda had joined on loan until the end of the season. He was seen as a temporary replacement for Antonio Cassano who had left to join Milan. Macheda made his debut for Sampdoria on 9 January in a 2–1 home victory over Roma. On 19 January, Macheda scored his first and only Sampdoria goal on his first start for the club, as he opened the scoring in their Coppa Italia tie against Udinese. Sampdoria won 5–4 in a penalty shootout as the game had ended 2–2 after extra-time. Unfortunately, the club's poor performances led to their relegation to Serie B. Following their relegation, Macheda's agent said he could make a return to Sampdoria, but the player himself ruled out a return to Italy in the 2011–12 season and stated that he would remain at Manchester United.