A full international between 2002 and 2012, he won 29 caps and scored one goal for the France national team and represented them at the 2003 FIFA Confederations Cup as well as UEFA Euro 2012.

[3] Roma was later found guilty of misconduct, as AJ Auxerre, his previous club, did not agree to the transfer; it was solely the decision of the player.

Roma's transfer misconduct in the purchase of Mexès led to the club's being suspended in 2005 from signing players other than free agents,[8] but the ban temporarily lifted in August.

Mexès, partnering with Matteo Ferrari, Cristian Chivu, and Christian Panucci on defence, helped Roma to a 7–4 aggregate victory, including a 6–2 first leg win.

At the 2008 Coppa Italia final, Mexès scored the opening goal for Roma, and the Giallorossi went on to win 2–1, defending their title.

[citation needed] With Mexès in defence, Roma qualified for the knockout stage of the 2008–09 UEFA Champions League.

Although he received slightly less playing time with the arrival of Nicolás Burdisso on loan from Inter, Mexès contributed to a defence, which helped Roma finish second in Serie A.

[citation needed] On 3 April 2011, Mexès had to be substituted early in the second half in a Serie A match with Juventus, because of an injury to his left knee.

He made 24 appearances for Milan in his debut season, and was the club's third choice central defender behind starting duo Alessandro Nesta and Thiago Silva.

Mexès and Zapata became Milan's first choice central defensive duo and conceded just 12 goals in the second half of the 2012–13 Serie A season.

[19] In November 2015, Mexès was nominated for the FIFA Puskás Award for his goal in an International Champions Cup friendly match against Inter, a well struck volley from the edge of the area, on 25 July 2015.

[20] On 14 May 2016, Mexès played his last game for AC Milan in a 3–1 loss against AS Roma at San Siro, in which he was also the team's captain.