Girard led Montpellier to their first French title last year but has left the club after four seasons to replace Rudi Garcia who joined AS Roma this week from the 2011 French champions.
"I knew him as a coach and for his achievements. I met a great, passionate and hard-working man," Lille president Michel Seydoux said in a statement on the club website.
"I am proud and happy that Rene has joined our club."
Lille did not disclose the length of Girard's contract but French media reports said he had signed a two-year deal.
Lille, who missed out on Europe by finishing sixth last season, face financial problems and must rely more on young players next term, a mission that fits Girard's credentials.
The outspoken 59-year-old coached France youth teams for six years before taking charge of Montpellier.
He steered a Montpellier squad made up mostly of players from the academy to an unexpected league triumph in 2012 and was voted coach of the year in France by his counterparts.
But Girard failed to meet higher expectations last season, when Montpellier finished bottom of their Champions League group and a disappointing ninth in the Ligue 1 table.