Benzema, 33, was taken off in the 39th minute at the Stade De France in what is France's last match before they take on Germany in their opening match of the European Championship next week.
The Real Madrid forward was replaced by Olivier Giroud and was captured by French television in pain as team doctors examined his right leg.
He had fallen heavily when attempting a header a few minutes earlier.
"It's a dead leg. He took a good hit on the muscle above the knee," France coach Didier Deschamps told broadcaster M6.
"He stopped playing because he felt it hardening... the medical staff are at his side."
The prolific star had been sidelined by Les Bleus since 2015 over his alleged role in a blackmail plot involving his former international teammate Mathieu Valbuena.
He missed out on France's 2018 World Cup win and their run to the Euro 2016 final on home soil.
Benzema has scored 27 goals for France and was last month named as this season's best French foreign-based player by the country's players' association.
He scored 29 goals last season for Real Madrid, passing 20 league goals in all three seasons since Cristiano Ronaldo left for Juventus in 2018.
Highlights karim benzema France Olivier Giroud euro 2020