The former Rennes coach returns to management more than two years after leaving the Breton side.
Lille have not revealed the length of Antonetti's deal at Stade Pierre-Mauroy, with further details to be revealed as he is presented to the media on Monday.
Herve Renard paid for a poor start to the season which garnered just two wins and left Lille 16th in the table with his job during the recent international break.
Patrick Collot oversaw Saturday's 1-1 draw at bottom club Troyes, which leaves Lille five points above the relegation places.
Antonetti's first task is to prepare Lille for next weekend's trip to fifth-placed Angers.