Resino had only taken only 11 points from a possible 45 since taking over from Joaquin Caparros in January and the Espanyol loss leaves Granada six points from safety with four games of the league season remaining.
“The results obtained by the team in recent days have forced this difficult decision to be taken,” said a statement on the official Granada website.
“Granada CF thanks Abel Resino for his work and professionalism and wishes him all the luck in the future.”
Former Atletico Madrid coach Resino had failed to win any of his last eight games in charge – three draws and five defeats – since a 1-0 home victory over Malaga on March 7.
The Andalusian club now plans to appoint a successor until the end of the campaign, probably as early as Friday afternoon before Sunday’s trip to Getafe.
Granada’s last three games of the season are at home to bottom-placed Cordoba and reigning champions Atletico, and away to David Moyes’ Real Sociedad.