With Puyol and Pique both out, the Argentine will be joined at the back by the new arrival from London, while Xavi is given a rest by the home side
The 2011-12 Primera Division runners-up are without both Carles Puyol and Gerard Pique for Saturday's clash, meaning Tito Vilanova has been forced to improvise in defence.
Argentina international Mascherano, already accustomed to playing in the deeper role, will be joined by the former Arsenal man inside full-backs Dani Alves and Adriano.
With Andres Iniesta also unfit and Xavi rested, Thiago and Cesc Fabregas join Sergio Busquets in the middle of the pitch.
Granada coach Juan Antonio Anquela must contend with a lengthy casualty list. The suspended Dani Martinez is joined on the sidelines by Fran Rico, Manolo Lucena and Hassan Yebda, all injured.
Barcelona (4-3-3): Valdes; Alves, Song o Bartra, Mascherano, Adriano; Busquets, Thiago, Cesc; Alexis, Messi, Villa.
Granada (4-2-3-1): Tono; Nyom, Siqueira, Inigo Lopez, Borja Gomez; Iriney, Mikel Rico; Brahimi, Orellana, Torje; Floro Flores.