He left the pitch in obvious pain and was taken for tests which have confirmed the extent of his injury and that he will miss what is arguably the most important game of the season.
Barca's triumph against Sevilla in the top-of-the-table clash came at a cost after Lionel Messi fractured his arm at Camp Nou.
Barcelona and Real Madrid have a lot at stake when they meet at Camp Nou on Sunday, but the first Clasico of the season will be haunted by the absence of two stars who have been at the forefront of the clash for nearly a decade.
However, those are three key individuals in their side that could be ruled out of action, and so it remains to be seen how Spalletti plugs those gaps with veteran Borja Valero likely to be forced to step in, as he did when replacing Nainggolan against AC Milan at the San Siro.
"We will notice his absence", Barcelona coach Ernesto Valverde said. "We know what he gives us and what we miss when he is not around".
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Luis Suarez made it 3-0 to Barca from the penalty spot shortly after the hour and although Pablo Sarabia threw Sevilla slim lifeline 11 minutes from time, Ivan Rakitic netted against his former club to put Barca 4-1 in front, before Luis Muriel netted in injury time to establish the definitive 4-2 in the score-line.
Meanwhile, Real Madrid suffered their fourth loss in five games and set an unwanted record with a 2-1 defeat by Levante at the Bernabeu.
On Monday, Marca listed six options in a "casting for replacements" - Ousmane Dembele, Rafinha, Munir El Haddadi, Malcom, Carles Alena and Sergi Roberto. Borja scored a goal in each half in Espanyol's 2-0 win away to Huesca, whose new coach Francisco debuted with a defeat after replacing Leo Franco during the worldwide break. "He is not yet fully aware of what it means to play at the highest level", said France coach Didier Deschamps last month.
The 25-year-old Argentina global - who has scored at least 20 league goals in three of the previous four seasons - is out of contract in 2021 with a reported €110million release clause for foreign clubs.