Grim Fandango is about Manny Calavera's quest to save himself and to find out what is going on in the Department of Death. This agency was assigned to provide souls with their just rewards. However, Manny realizes that his best clients don't get their just reward, a ticket on the Number Nine. He also sees that his competitor Domino Hurley, gets all the best clients and they get a ticket on the Number Nine. Even those souls who don't deserve a ticket, seem to get it.

Manny struggles with cases that can give him no commission and therefore he's stuck in the Eighth Underworld. Once a top salesman, Manny now finds himself scraping the bottom of the barrel

Manny then acquires a client with an almost perfect record. Unfortunately, for Manny, she doesn't seem to qualify for the best travel package. Manny suspects that this is foul play and goes to check it out. Mercedes, Manny's client, runs off and then Manny must find her in order to get a commission and get out of the Eighth Underworld. Manny sets off on a four-year journey, attempting to find Meche. Along the way, Manny forgets all about the commission and just wants to get out of the Eighth Underworld and save Meche. When he discovers that something is amiss in the Afterlife, Manny must match wits with Domino and an unseen force, Hector LeMans.

Manny then becomes a crusader for all those souls wronged by LeMans' evil dealings, returning to El Marrow to find that LeMans rules it like a King.

Manny visits such exotic and strange locations as the Petrified Forest, Rubacava, the Edge of the World and El Marrow. And all the while, Manny finds himself in many different roles : Captain of the S.S. Limbo, A Casino manager, a travel agent, Grim Reaper and much more.