Messi, who missed the start of the season with a calf injury, made his first appearance of 2019-20 as a substitute in the goalless Champions League draw away to Borussia Dortmund in midweek.
But with coach Ernesto Valverde easing the club captain back into action, Messi remains out of the starting XI for the trip to Nuevo Los Carmenes.
Luis Suarez starts after making a goalscoring return to fitness from the bench against Valencia last weekend, featuring in attack with Antoine Griezmann.
There is no place in the Barcelona side for teenager Ansu Fati, who has two LaLiga goals already this season, with Carles Perez replacing him in the XI.
With Jordi Alba sidelined by injury, left-back Junior Firpo makes his first LaLiga start since joining Barcelona from Real Betis, while Ivan Rakitic is in a LaLiga line-up for the first time this season.
Barca have taken a single point from their two away games in the league, following an opening weekend loss at Athletic Bilbao with a 2-2 draw at Osasuna.
However, the Spanish champions have won 15 of their past 16 LaLiga matches against Granada, including each the previous six with 21 goals scored and only two conceded in that run.