Pique twisted his ankle badly after being fouled by David Silva during Barcelona's 4-0 win over Manchester City in a Champions League match on Wednesday, and tests on Thursday showed he will be out of action for around three weeks, reports Xinhua. [La Liga 2016/17: Schedule of game week 9]
The 29-year-old has been Barcelona's best defender this campaign, and his loss is a problem for a defence which has looked unsteady at times this season.
Jordi Alba will also miss the trip to face his former club with a recurrence of the hamstring problem which he picked up during the last international break.
Lucas Digne will replace Alba, but there is also some good news: the return of Sergi Roberto will allow Javier Mascherano to move back into the centre of the defence where he will probably partner Samuel Untiti.
With league leaders Atletico Madrid travelling to third place Sevilla, the Valencia game gives Barcelona the chance to climb up the table.
The attacking trident of Lionel Messi, Neymar and Luis Suarez will, as usual, be their main threat, while Paco Alcacer will wait for his turn from the bench as he returns to face the club he left this summer.
Barcelona will need to be wary of a Valencia side which looked much improved when they won 2-1 away to Sporting Gijon last weekend.
That win was the coaching debut of former Italy coach Cesare Prandelli and the Italian looks to have upped the physical level of his squad since taking over and imposing more tactical discipline.
This incorporates Mario Suarez and Enzo Perez providing cover for a pact attack which includes Nani, Rodrigo, Joao Cancelo. Forward Munir, on loan to Valencia for Barcelona, is currently struggling for game time.