He is cousin of fellow footballer Alessandro Santos, who played for Japan[2]- Santacroce was a youth product of Calcio Como SpA.

During the January 2008 transfer window, Serie A club Napoli completed the signing of Santacroce in a permanent move, for €5.5 million,[8] 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.

At the start of 2011–12 Serie A, Napoli sent Manuele Blasi and Santacroce to Parma as part of the compensation of signing Blerim Džemaili (€9 million).

[12] 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.

In 2008–09, Santacroce was confirmed as a Napoli regular, and his performances were quickly noted by new Italy head coach Marcello Lippi, who on 5 October 2008 called him to join the azzurri squad for the FIFA World Cup 2010 qualification matches against Bulgaria and Montenegro.

[24] Santacroce dedicated his first senior call-up to his former Como youth team coach Stefano Borgonovo, who was battling amyotrophic lateral sclerosis at the time, succumbing to the disease in 2013.