On 10 December 2009, the DRC awarded Udinese liable to receive €3,933,134 from De Sanctis, quoting Matuzalém's case as legal reference.

[10][11] He had aided to Roma's perfect start to the Serie A season, keeping nine clean sheets in the first ten games, conceding just once as they topped the table on 30 points.

During the 2013–14 season, he went 745 consecutive minutes without conceding a goal in the Italian top-flight; he currently holds the joint seventh-highest unbeaten streak in Serie A, alongside Luca Marchegiani.

[12] He made his debut for the club on 26 July, in the first leg of the Third qualifying round of the UEFA Champions League against Fenerbahçe, but was forced off in the 12th minute of the eventual 2–1 away defeat after sustaining an injury.

[17] On 26 April 2017, he started in the club's 5–0 defeat to eventual champions Paris Saint-Germain in the Coupe de France semi-final.

[20] At youth level, De Sanctis represented the Italy under-21 side on seven occasions between 1999 and 2000,[21] and won the 2000 UEFA European Under-21 Championship with the team.

[24] 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.

[25][26] 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.

[22][23] 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.

[26][32] 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.

[51] He was dismissed from his post on 3 January 2025, together with his collaborator Giulio Migliaccio, due to Palermo underperforming in the first half of the season and him being publicly criticised by the local supporters.