Mustafi began his career in the youth ranks of Hamburger SV and English club Everton, where he made one substitute appearance for them before leaving to Sampdoria in January 2012.

Mustafi was born in Bad Hersfeld, Hesse,[4] to a Macedonian Albanian family originally from Gostivar in the former Yugoslavia.

[7] He later stated that "Goodison Park feels like home", after turning down offers from Manchester City and Newcastle United.

[8] Mustafi made his competitive debut on 16 December 2009, replacing Tony Hibbert in the 75th minute of a 0–1 home loss against BATE Borisov, for the season's UEFA Europa League.

[11] Mustafi was released by Everton after he asked manager David Moyes to allow him to move on for more game time.

[15] On 7 August 2014, Mustafi signed a five-year deal with La Liga's Valencia CF, for an undisclosed fee,[16] rumoured to be €8 million.

[20] On 3 March 2016, Mustafi received a straight red card in the first half of Valencia's 7–0 loss at Barcelona in the first leg of the Copa del Rey semi-final, after conceding a penalty with a foul on Lionel Messi.

[21] On 30 August 2016, Mustafi joined English club Arsenal for an undisclosed fee, reported to be in excess of £35 million.

[41] On 2 September 2021, Mustafi returned to the city of Valencia, joining La Liga club Levante on a two-year deal.

[45] He was confirmed to have been released by the club on 10 July 2023 after his contract expired [46] and retired on 25 June 2024 to become the assistant coach of the German U17 national team, having not played senior football after leaving Levante.

[48] Eligible to represent Germany, North Macedonia and Albania,[49][50] Mustafi played for his country of birth at youth level; with the under-17 team he won the 2009 UEFA European Under-17 Championship.

[55] He appeared as a substitute in Germany's opening World Cup game against Portugal, coming on in the 73rd minute in place of Mats Hummels to win his second cap.

[57] He was selected to start at right-back in Germany's round of 16 match against Algeria, but was substituted in the 70th minute for Sami Khedira due to an injury in his left thigh.