Netherlands boss Ronald Koeman admitted it will be "very difficult" for Memphis Depay to return to fitness for Euro 2020.
Lyon captain Depay ruptured the anterior cruciate ligament in his left knee during the French club's Ligue 1 loss to Rennes on Sunday.
The 25-year-old former Manchester United forward had been set to play a leading role in his nation's first appearance at a major tournament since the 2014 World Cup, but the odds of him figuring are now remote.
It was a bad weekend for Netherlands boss Koeman, who could also be without Donyell Malen after the promising PSV striker suffered a suspected knee injury in an Eredivisie defeat to Feyenoord.
"It was not a fun Sunday," Koeman told NOS.
"It is known that Memphis has had an incredibly high return over the last two years, certainly with the Dutch national team, and is a very important player.
"But in the end he is the one who has to deal with this setback. Of course we do too, but I know how he proud he was to be going to the European Championship. It is a great blow to him."
Depay hit six goals in as many Euro 2020 qualifiers for Netherlands and had added 14 in all competitions for Lyon this term before the injury struck.
Koeman continued: "It is clear that it is a cruciate ligament injury and that means months of rehabilitation... [to] come back, train, play matches, it takes a little time.
"Then a European Championship might be very difficult. On the other hand, I learned that it makes no sense to look ahead. Also, this Sunday proved that you can't count on anything.
"Let's hope everyone else stays fit and healthy and then by May we will see how it looks for us."