All eyes will be on the 61-year-old to see which players he chooses in his starting XI and how the team fare under their new boss.
Let’s have a look at who might feature on Sunday:
Goalkeeper Marc-Andre ter Stegen has been back in training this week and may return to action after being sidelined with a knee problem. Neto is available if there are any doubts at all about the German’s fitness.
Setien has decisions to make over his backline with no injuries reported. Nelson Semedo and Sergi Roberto are the choices at right-back, while the new boss must also decide on whether Clement Lenglet or Samuel Umtiti will partner Gerard Pique. Of course he could also decide to play with three centre-backs.
At left-back we should see Jordi Alba continue, but Junior Firpo will be feeling he may get more first-team opportunities this season under his former Real Betis manager.
Riqui Puig has made headlines all week since Setien took over and will be hoping for his first La Liga minutes of the season on Sunday.
Arthur has been back in training but it’s unclear if he’s fully fit for this game, while Frenkie de Jong is suspended after being sent off against Espanyol.
Sergio Busquets, Ivan Rakitic and Arturo Vidal are the other options in midfield, which is the area of the team likely to provide the most talking points when the line-ups are released.
Barcelona will have to cope without Luis Suarez for the next four months after knee surgery which means Antoine Griezmann is likely to be shifted to a more central role.
Lionel Messi will captain the team as usual which just leaves one more spot available in the XI.
Ansu Fati looks the most likely player to start, although Carles Perez, Abel Ruiz and Alejandro Marques have all trained with the first team this week.
Possible starting XI: Ter Stegen; Semedo; Pique, Lenglet, Alba; Vidal, Busquets, Puig; Messi, Griezmann, Ansu.
How do you think Barcelona will line up against Granada? Let us know your thoughts, predictions and line-ups in the comments below!