In March 2010, Chievo teammate Sergio Pellissier confirmed that Yepes would join Milan in the summer, when his contract ran out.

Yepes got to Milan in the 2010–11 season but was quickly deployed as a substitute due to the starting centre-back being Thiago Silva.
Yepes played few games in the Italian Serie A, but participated in the UEFA Champions League.
Yepes was close to scoring with Milan in the UEFA Champions League match against Tottenham Hotspur, in which he had two clear chances of scoring with a header, but was denied twice by Tottenham keeper Heurelho Gomes.

Yepes scored his first goal for Milan on the 23 October 2011, where he finished off a comeback against Lecce, scoring the fourth and winning goal for Milan in the 83rd minute to drive the Rossoneri to a 4–3 victory, with Kevin-Prince Boateng scoring a hat-trick to level the scores after a 3–0 losing position.

On 12 May 2012, Yepes signed a one-year extension contract with Milan, keeping him at the club until the summer of 2013.
After being an irregular player during the following season, however, Yepes stated that he would not sign a new contract with the club despite being offered the chance, expressing that he needed more "guaranteed" playing time in order to better prepare himself for the 2014 FIFA World Cup.
He later confirmed that Milan would not offer him as such and his reason for departure.
In March 2010, Chievo teammate Sergio Pellissier confirmed that Yepes would join Milan in the summer, when his contract ran out.
Yepes got to Milan in the 2010–11 season but was quickly deployed as a substitute due to the starting centre-back being Thiago Silva. Yepes played few games in the Italian Serie A, but participated in the UEFA Champions League. Yepes was close to scoring with Milan in the UEFA Champions League match against Tottenham Hotspur, in which he had two clear chances of scoring with a header, but was denied twice by Tottenham keeper Heurelho Gomes.
Yepes scored his first goal for Milan on the 23 October 2011, where he finished off a comeback against Lecce, scoring the fourth and winning goal for Milan in the 83rd minute to drive the Rossoneri to a 4–3 victory, with Kevin-Prince Boateng scoring a hat-trick to level the scores after a 3–0 losing position.
On 12 May 2012, Yepes signed a one-year extension contract with Milan, keeping him at the club until the summer of 2013. After being an irregular player during the following season, however, Yepes stated that he would not sign a new contract with the club despite being offered the chance, expressing that he needed more "guaranteed" playing time in order to better prepare himself for the 2014 FIFA World Cup. He later confirmed that Milan would not offer him as such and his reason for departure.
Mario Yepes