On 22 November 2015, Antonetti was appointed as head coach of Lille in place of Hervé Renard, signing a three-year contract. His first competitive match was a Ligue 1 away match against Angers on 28 November 2015, which ended in a 2-0 win for Angers. When Antonetti took over as head coach, Lille was in 17th position in the Ligue 1 table. After struggling during the first three months of Antonetti's tenure, Lille finished the season superbly, finishing fifth in the 2015–16 Ligue 1 and runners-up to Paris Saint-Germain in the 2015–16 Coupe de la Ligue. At the end of August 2016, he signed an extension to his contract that would tie him to the club until 30 June 2020. On 22 November 2016, the club announced that they had parted company with Antonetti and that he had agreed to leave "in a friendly manner". Antonetti would receive a severance payout of about 840,000 euros, which was equivalent to seven months of his gross monthly salary of 120,000 euros. At the time of Antonetti's departure, Lille was languishing in 19th position (second from bottom) in the 2016–17 Ligue 1 table. They were also eliminated at the first hurdle of the 2016–17 UEFA Europa League, in the third qualifying round against Gabala FK.