The 30-year-old picked up a muscle injury in last weekend's 2-1 defeat at Atletico Madrid and has been ruled out for 15 days after featuring in all 22 league games this season.
Barca's first defeat in La Liga allowed Real Madrid to close to within two points at the top.
"Xavi is a very important player for us, he's the one who controls the rhythm of games," fellow midfielder Sergio Busquets told reporters.
"He is the essence of this Barcelona side. We hope we don't miss him too much."
Xavi's setback was the latest in a string of recent muscle injuries for the squad that have seen Yaya Toure, Dmytro Chygrynskiy, Daniel Alves and Seydou Keita struck down.
Coach Pep Guardiola, who has one eye on next week's return to Champions League action at VfB Stuttgart, will be cautious about rushing players back into the side, but does have Gerard Pique and Rafael Marquez back from suspension.
His main concern will be to get their trademark quick-passing game working effectively again without Xavi, after their below-par showing at the Calderon.
TOUCHING DISTANCE
Real Madrid's joy at seeing Barcelona brought to within touching distance last weekend was tempered by their 1-0 defeat away to Olympique Lyon in a Champions League last-16 first leg match on Tuesday.
Manuel Pellegrini's side, who host Villarreal on Sunday, were a shadow of the side that has been sweeping all before them in La Liga and will be looking to resume normal service in front of their own fans.
"The game against Villarreal is very important against a rival that is getting stronger day-by-day," Real defender Alvaro Arbeloa told reporters.
"It's here where we need to try and recover our form."
Real have a 100 percent record in the Bernabeu but will be wary of a Villarreal side who, although they lie 10th, were expected to be pushing for a top four finish this year.
Coach Ernesto Valverde was sacked at the beginning of the month and his replacement Juan Carlos Garrido, a former understudy of Pellegrini's at Villarreal, earned his first victory at the helm last weekend.
Ten points back in third lie Valencia, who visit Getafe in the newly re-instated Monday night game.
Close on their heels are Sevilla who visit fifth-placed Real Mallorca on Saturday seeking to become the first side to win a point at the Ono Estadi this season.
