Lyon star Memphis Depay suffered a ruptured anterior cruciate ligament in his left knee during Sunday's Ligue 1 loss to Rennes, the club confirmed.
Depay, 25, is set to miss the rest of the season and becomes a major doubt for Netherlands' Euro 2020 campaign after being substituted at half time during the 1-0 defeat.
The forward has enjoyed a fine Ligue 1 campaign, scoring nine goals and providing two assists in 13 games, but he faces at least six months out of action.
"It's a very bad evening because we lost and because of the lack of quality. The very bad news is also the injury of Memphis, who could be out for a while," Lyon sporting director Juninho said.
"He's our captain and I'm sad for him."
Depay's injury was made worse when Rennes scored the winning goal in the 89th minute, with 17-year-old rising star Eduardo Camavinga getting his first league strike.
Making matters worse for Lyon, midfielder Jeff Reine-Adelaide suffered a ruptured ACL in his right knee - coming from the field during the first half.
Confirming both injuries, Lyon said in a statement the pair were "unfortunately likely to be unavailable for at least six months".
Lyon are eighth in the Ligue 1 table after two defeats at home to Lille and Rennes in their past three league matches have seen them tumble down the standings.
The likely loss of Depay for the Netherlands' European campaign will hurt the nation, with the former Manchester United forward scoring six goals and getting 10 assists in 2019.
Luuk de Jong, Wout Weghorst or Myron Boadu will be first line to fill Depay's shoes, but the trio only has six goals between each other in 27 caps for the Oranje.
The Netherlands have been on the rise over the past 12 months since overcoming the disappointment of missing the 2018 World Cup.
They reached the final of the first ever UEFA Nations League, losing 1-0 to Portugal, and have recorded wins against Germany (twice), France and England.