At international level, Milito earned 25 caps for Argentina, scoring 4 goals, and represented his country in two Copa América tournaments and 2010 FIFA World Cup.

Milito started playing at Argentine first division team Racing Club in 1999, where he won the 2001 Apertura tournament.

[3] Due to this, Milito was forced to leave Genoa and would ultimately join his brother Gabriel at Real Zaragoza in the Spanish La Liga.

[9] He scored 23 goals, two fewer than league top goalscorer Ruud van Nistelrooy and three behind European Golden Boot winner Francesco Totti.

[14][15] His agent, Fernando Hidalgo, confirmed Milito chose explicitly to return to Genoa despite having received more lucrative offers from other major European clubs.

[3][20] On 20 May 2009, La Gazzetta dello Sport confirmed that Diego Milito was transferred to Inter Milan alongside teammate Thiago Motta.

The striker adapted to his new surroundings quickly and had an excellent start to his Inter career, scoring two goals in a 2–0 World Football Challenge win over city rivals Milan.

[31] The consistency which Milito had shown at his previous clubs was sustained throughout his debut season at Inter, and after the first few matches, he had established himself as a key contributor to the squad.

On 30 October, in a 5–3 home victory against Palermo, Milito, who had returned from an injury, came off the bench to make the result safe, scoring Inter's fifth goal.

Three days later, on 4 November, he scored his first goal in the UEFA Champions League in a 2–1 Group Stage win over Dynamo Kyiv; it was the equaliser which led to Wesley Sneijder's game-winner in the 89th minute.

[34] On 24 February, in another Champions League match, this time in a 2–1 Round of 16 win against Chelsea, he scored another important goal, his second in the competition.

[35] Four days later, Milito netted the matchwinner which gave Inter Milan a 3–2 victory at Udinese, in a thrilling win for the Nerazzurri.

[36] On 27 March, after missing a 3–0 win over Livorno[37] with a hamstring problem, Milito returned for a crucial battle at title contenders Roma, where he scored one goal in a 2–1 loss.

The Argentine first scored the only goal in Inter's victory over Roma in the final of the Coppa Italia on 5 May 2010, enabling the Nerazzurri to take home their first trophy of the season.

[43] Eleven days later, it was also Milito's goal which secured Inter Milan's 18th Scudetto when they beat Siena 1–0 on the final matchday of Serie A.

As a result, Inter became European club champions for the first time in 45 years with a 2–0 victory and completed their historic treble championship season.

[50] Eight days later, on 22 September, Milito scored his first goals of the season in a 4–0 win against nearly promoted club Bari at San Siro, helping the team to reach in top of the league.

[52] He dedicated the goal to his teammate Walter Samuel, who three days ago ended his season after suffered a severe knee injury.

[53][54] In December, Milito scored a goal against Seongnam Ilhwa Chunma in the semi-finals of the 2010 FIFA Club World Cup; Inter went on to win the tournament.

[72] Two days later, Milito announced that the surgery to repair the injury was a success, but that the player would not return to the pitch for at least six months, ruling him out of contention for the remainder of the season.

[76] Milito scored on his Racing return to help the team to a 3–1 win over Defensa y Justicia on the opening weekend of the Argentine championship.

[77] On 26 August 2014, he scored a crucial goal with a penalty in the 1–0 victory against Arsenal de Sarandí in week four of Argentine Primera División.

[94] On 1 June 2011, Milito was included in new Albiceleste manager Sergio Batista's 23-man squad ahead of the 2011 Copa América,[95] along with his brother Gabriel and Inter teammates Javier Zanetti and Esteban Cambiasso.

[87] A quick, dynamic, and technically gifted forward, with good vision, composure, and an eye for goal,[97] Milito was known for his offensive movements and ability in the air, and was capable of finishing well with his head as well as both feet, despite being naturally right-footed.

Regarding his elegant yet efficient playing style, and his consistent, prolific goalscoring,[102] Goal.com said of Milito in 2010: "His profession is football and his speciality is goals.

[4] Scoring goals on the biggest stages for a marquee team finally earned the striker the recognition merited by his skill and goalscoring record.

Under his management, great players were brought in and a good sports project was consolidated in which he won two titles: Superliga 2018/19 and Trofeo de Campeones 2019.

Milito has considerable Italian roots; his paternal family emigrated to Argentina from Terranova da Sibari, Calabria.