Gilles Muller has won 11 Challenger trophies in singles and 3 in doubles in his career.

In 2016 Gilles played 2 ATP finals: the first in 's-Hertogenbosch, defeated by Nicolas Mahut, the second in Newport, defeated by Ivo Karlovic.

On January 14, 2017, at the age of 33, he won his first career tournament, beating Daniel Evans in the final of the Apia International Sydney. A few months later, on May 7, he lost the Estoril final against Pablo Carreño Busta. On 18 June of the same year he also won his second title, in 's-Hertogenbosch, after defeating Ivo Karlović in the last act of the tournament.

On 10 July he beat Rafael Nadal in the match that lasted almost 5 hours valid for access to the quarterfinals of the Wimbledon Tournament, with a score of 6-3 6-4 3-6 4-6 15-13. He had never passed the third round of this tournament in his career (best result obtained in 2005, always beating Nadal in the second round). He was then defeated in the quarterfinals by Marin Čilić, in five sets.

He has been part of Davis' Luxembourg team since 2000: he currently holds Luxembourg's record for total wins (51), singles wins (32) in the event and, with compatriot Mike Scheidweiler, forms the most successful doubles in Luxembourg Davis history , with 20 fight wins. He represented the country at the 2003 Games of the Small States of Europe, winning two gold medals, in singles and doubles, partnering Mike Scheidweiler. He also participated in an Olympic edition (2016) in singles, where he came out in the third round.

He retired in 2018, aged 35.