Born in Bernal, Buenos Aires Province, Milito started playing professionally with Primera División side Independiente in 1997.

[11] Italian newspaper Tuttosport published an interview in June 2007 in which Milito – who holds the country's passport through descent – said that he wanted to leave for Juventus.

[17] On 5 January 2010, he made his return to competitive football in the first leg of the Copa del Rey's round of 16, a 1–2 home loss against Sevilla.

[19] Milito contributed one goal to a 5–1 home win against Ceuta in the domestic cup on 11 November 2010 (7–1 on aggregate), but had to leave the game injured.

[20][21] On 30 April 2011, starting in a league match at Real Sociedad, he had a goal wrongfully ruled out for offside with the score at 1–1, as the hosts went on to win it 2–1;[22] as a result of his action he also tore a calf muscle, being sidelined for the rest of the season[23] and making ten appearances for the eventual champions.

[27][28][29][30][31] On 20 August 2010, national team coach Sergio Batista recalled Milito for a friendly with Spain the following month, the player's first international appearance in more than three years.

[38] Milito started his first coaching adventure outside Argentina on 9 August 2017, signing for two years with O'Higgins from the Chilean Primera División.

[39] He returned to Estudiantes on a three-year deal on 11 March 2019[40] but, one year later, after being ousted in the round of 64 of the Copa Argentina by lowly Deportivo Laferrere, he again resigned.

[41] In January 2021, Milito signed a three-year contract at Argentinos Juniors, replacing Diego Dabove who had moved to San Lorenzo.

[44] On 24 March 2024, Milito was announced as head coach of Brazilian club Atlético Mineiro, agreeing to a deal running until December 2025.