Barcelona have confirmed that midfielder Rafinha ruptured the anterior cruciate ligament in his left knee in the club's 1-1 draw with Atletico Madrid on Saturday and will undergo surgery this week.
The 25-year-old played the second half of the game at Wanda Metropolitano, where Ousmane Dembele's last-minute equaliser cancelled out Diego Costa's 77th-minute opener for Atletico.
Rafinha was a second-half substitute for Sergi Roberto, who suffered a hamstring injury in his left leg and is expected to be out for between three and four weeks.
The double injury blow comes ahead of a sequence of four matches in 11 days for Barcelona, who face PSV in the Champions League before entertaining Villarreal at home in LaLiga.
Ernesto Valverde's men then take on Cultural Leonesa in the Cope del Rey ahead of a derby match against Espanyol away from home.
Rafinha has started only three of Barcelona's 13 league games so far this season, with Valverde preferring Sergi Roberto or Ivan Rakitic on the right side of midfield.
With both players absent, the Barca head coach may opt to utilise Arturo Vidal in the role, the Chilean having made only three league starts since joining the club from Bayern Munich.
Barcelona are top of the league but missed the opportunity to widen their lead over second-placed Atletico, who trail them by a single point.