Luis Suarez will be out for four to six weeks after undergoing surgery on a knee injury, Barcelona announced on Friday.
Suarez will miss the Copa del Rey final against Valencia on May 25 and also faces a fight to be fit for the Copa America in Brazil next month.
Uruguay's first game is against Ecuador on June 16, just over five weeks after Suarez had the operation on Thursday.
"Suarez was subjected last night to an arthroscopy on the right knee due to an internal meniscal injury," read a club statement released on Friday.
"His approximate time out will be between four and six weeks."
Suarez has a better chance of playing in Uruguay's second and third group games, against Japan on June 20, and defending champions Chile on June 24.
But his absence from the cup final in Seville is a major blow to Barcelona, who can secure their second domestic double in as many years by beating Valencia.
Suarez will also miss Barca's final two La Liga games at home to Getafe on Sunday and away to Eibar the following weekend.
The striker played the full 90 minutes of Tuesday's shock 4-0 defeat to Liverpool, which ended the club's hopes of reaching the Champions League final.
Suarez has scored 21 goals in La Liga this season, fewer only than Lionel Messi, and 27 in all competitions.
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