The defender hoped to be available after sitting out the last five La Liga games - two of the latest being draws.
However, the club announced on Thursday that Mathieu is unlikely to be available again until the middle of December at the earliest.
"During the final stages of his recovery, Jeremy Mathieu has suffered a recurrence of the injury to the soleus in his right leg," the club said in a statement.
"According to the FC Barcelona Medical Services, this means he'll be sidelined for a further 15 to 20 days.
"That means the French defender will be unavailable for the forthcoming games against Real Madrid, Borussia Monchengladbach and Osasuna."
The news is a blow to Luis Enrique, who has a number of injury concerns ahead of the visit of the league leaders to Camp Nou.
Captain Andres Iniesta is battling to be fully fit after spending more than a month out with a knee injury, while defenders Samuel Umtiti, Gerard Pique and Jordi Alba will face tests later this week.