At youth level, De Sanctis represented the Italy under-21 side on 7 occasions between 1999 and 2000, and won the 2000 UEFA European Under-21 Championship with the team. De Sanctis never became a regular in the Italian senior national team due to the consistency of Gianluigi Buffon, and therefore often served as a back-up keeper. De Sanctis made his senior international debut for Italy on 30 March 2005, under manager Marcello Lippi, in a 0–0 friendly draw against Iceland. Although he did not make Lippi’s 23-man squad for the 2006 FIFA World Cup, he was chosen as one of the four back-up players to be called up in the event of an injury to Buffon, Angelo Peruzzi or Marco Amelia, After the 2006 FIFA World Cup, he secured a place as the team’s number two goalkeeper to travel with the Italian squad to UEFA Euro 2008, under Roberto Donadoni, as well as the 2009 FIFA Confederations Cup and the 2010 FIFA World Cup, under Lippi. Although Buffon suffered an injury in the opening match of the latter tournament, De Sanctis did not feature in any matches, as Federico Marchetti was instead chosen to start; Italy were eliminated in the first round. The team’s subsequent coach Cesare Prandelli preferred to include younger understudies, such as Antonio Mirante and Salvatore Sirigu, to Buffon, instead of De Sanctis. However, after injury to Emiliano Viviano, De Sanctis returned to the squad as Buffon’s back-up for UEFA Euro 2012 qualifying matches in September 2011, and also appeared in Italy’s 3–0 friendly win against Northern Ireland in Pescara on 11 October, three years after his last cap for Italy. He eventually made the squad for the final tournament, but did not play, as Italy reached the final. His final match for Italy came on 16 October 2012, in a 3–1 win over Denmark in a 2014 World Cup qualifier. On 26 March 2013, the day of his 36th birthday, he announced that he would be retiring from international football after Italy’s World Cup qualifier against Malta later that day. In total, he made 6 appearances for Italy.