During the 2005–06 season, he scored his first Serie A goal for Sampdoria on 18 January 2006 against his boyhood club Fiorentina and made his European debut in the UEFA Cup in September.

"[9] He spent the first half of the 2011–12 season in Serie B with Sampdoria,[9] but on 31 January 2012, he was signed by Inter on loan with an option to buy, as a replacement for Thiago Motta.

[9] However, it seemed that he was set to leave the club in the summer of 2012, and was even linked with several other Italian sides;[13] after no other offers, he remained with Sampdoria the following season,[14] started to play regularly and managing to get his contract renewed twice until his retirement.

[16] Palombo was in the Italy U-21 team that won the 2004 UEFA European Under-21 Championship and achieved bronze medal of the 2004 Summer Olympics football tournament.

[17][18] Palombo made his Italy national team debut in the 0–2 defeat to Croatia on 16 August 2006,[6] coming as a substitute for Fabio Liverani in the 58th minute.

After a good 2009–10 season at club level, Marcello Lippi named him in the final 23-man squad for the 2010 FIFA World Cup.