Barcelona's struggles in recent weeks mean they now trail Real Madrid in La Liga and the midfielder suspects defeat on March 23 would end their hopes of retaining their title
The 1-0 reverse at Villarreal last weekend was the reigning champions' third loss in their last six league matches, a run that has seen coach Gerardo Martino's future questioned in some quarters.
The Catalans moved into the quarter-finals of the Champions League with a 4-1 aggregate win over Manchester City on Wednesday and get back to league action when they host Osasuna on Sunday, but Busquets has already set his sights on the Clasico seven days after that clash.
"We have come from an adverse outcome that makes it tough to win the league, but we still have to go to the Bernabeu and fight until the end," the midfielder told Marca.
"We are four points behind and it seems we cannot fight for the title, but the game at the Bernabeu will decide everything.
"If we win, we keep fighting, but if we lose then the league will be over."
The Catalans will head to the Santiago Bernabeu third in the table and four points adrift of Carlo Ancelotti's leaders, with Atletico Madrid sitting second, if all three times win this weekend.