Fabregas also started against Italy in the defending champions' first group match that ended in a 1-1 draw, sparking criticism against coach Vicente del Bosque for fielding a team without a recognized striker.
Spain's lineup is otherwise unchanged from the team that started the 1-0 win over Croatia in their last group game.
To combat Spain's strength in midfield, France has dropped forwards Samir Nasri and Hatem Ben Arfa, preferring to move right back Mathieu Debuchy into a five-man midfield. Karim Benzema is the lone striker as Les Bleus play their first match since a 2-0 loss to Sweden that led to a heated dressing-room bust-up.
Yohan Cabaye and Florent Malouda return in central midfield alongside Yann M'Vila, while Laurent Koscielny replaces the suspended Philippe Mexes at centre back to make his first competitive start. Veteran defender Anthony Reveillere is at right back.
France has been grappling with the fallout from the loss to Sweden, which coach Laurent Blanc acknowledged had set back preparations for the Spain game.
The winner of the third quarterfinal will play Portugal at Donetsk's Donbass Arena on Wednesday.