He finished as the losing side in the round 16 of 2004 Primavera Reserve League.
He plays in the centre or on the left of defence. Como
Santacroce was a youth product of Calcio Como Società per Azioni. He was in the starting lineup alongside future Serie A players Marco Parolo, Giuseppe Greco and Daniele Padelli. Parolo and Santacroce were promoted to Como first team in 2004, as the club had faced financial difficulties as well as relegation from Serie Bachelor in 2004.
Santacroce remained with the club in the whole 2004-2005 Serie C1 despite they were declared bankrupt on 22 December 2004.
Santacroce was in the starting XI in Como"s relegation "play-out", which the playoffs matches Como losing to Novara in 1–2 aggregate. Como folded at the end season as a takeover bid was denied.
Santacroce moved to Brescia as free agent and played for their Primavera team before making his first team debut for the rondinelle in a Serie B game on 23 April 2006, against Cesena. He played at Brescia from 2005 to 2007, also ensuring a place in the Italian U-21 team due to his impressive performances with the Lombardian side.
During the January 2008 transfer window, Serie A club Napoli completed the signing of Santacroce in a permanent move, for €5.5 million, becoming the third Brescia player to join the azzurri that year, the other two being Marek Hamšík and Daniele Mannini.
He quickly established himself into Napoli"s regular lineup, forming a valid defense duo with team captain Paolo Cannavaro, and playing very well throughout the remainder of the season. Santacroce has been described by a number of people in Italy, including Napoli President Aurelio De Laurentiis, as the "new Alessandro Nesta" That half season he started 13 times as well as 27 times in 2008-2009 Serie A. However after the arrival of Hugo Campagnaro, Walter Mazzarri started to fix its 3-men defense to Salvatore Aronica, Campagnaro and Cannavaro. Parma
At the start of 2011-2012 Serie A, Napoli sent Manuele Blasi and Santacroce to Parma as part of the compensation of signing Blerim Džemaili (€9 million).
Santacroce went on loan for €100,000.
He was largely used as a back-up central defender and made 12 league appearances, which was enough to secure him a move to Parma in a co-ownership deal for €900,000 in 4-year contract in July 2012. Santacroce wore no.13 shirt that season, changing from no.33.
Following the 2012-2013 Serie A season, the remaining half of Santacroce"s ownership was purchased from Napoli by Parma for free. The club now owns him outright.
On 6 August 2013 Santacroce left for Padova in a temporary deal.
Santacroce was given no.3 shirt of the first team