The player must control the Character and complete the level. The player may need to solve puzzles and pass obstacles.
Manuel Calavera, nicknamed Manny, works at the Department of Death in the town of El Marrow. After his boss, Don Copal, threatens to fire him for getting bad clients, Manny steals a client from Domino Hurley, his co-worker. She is called Mercedes Colomar, nicknamed Meche, but is assigned to the four year journey instead of tickets for the Number Nine Luxury Express Train, which Manny thinks she deserves. After Meche sets off, Manny discovers that Domino and Don have rigged the system, hoarding the tickets for Hector LeMans, the boss of the Criminal Underworld. Manny gets his friend and driver, Glottis, and sets off towards the Petrified Forest to find Meche. Manny finds Salvadore Limones, nicknamed Sal. Sal is the leader of the Lost Souls Alliance, who are aware of the Double Nine Ticket Scandal, and recruit Manny to help stop Hector. Manny, however, gets to the city of Rubacava before Meche, leaving him to wait.
A Year later, the City of Rubacava has grown, and Manny owns Cafe Calavera, which also contains a Nightclub and Casino. Olivia Ofrenda tells Manny that Don has been sprouted (A Method of destroying the dead by many plants grown in them and destroy their body) after letting the scandal become known. She also told Manny that Meche was spotted with Domino on a boat leaving the City. Manny follows them to a Coral Mining Plant, and discovers it to be a trap. He notices that others that have had their Double Nine tickets taken off them are being used for slave labour. Manny rescues Meche and the Slaves, and destroys Domino by making him go into a rock crusher. They all then go to the End of the World.
Manny, Glottis and Meche travel for a year, and reach the terminus for the Number Nine Train. The Gatekeeper of the Ninth Underworld does not let them past, since he believes they have sold their tickets. Glottis is in a critical condition, and needs serious medical attention. Demons at the terminus inform Manny that to restore Glottis to a normal conditon, they have to travel at a very high speed. They construct a makeshift rocket cart, and travel to Rubacava, with Glottis being better again.
They all return to El Marrow, but find that Hector has full control of it and has renamed it Nuevo Marrow. They regroup with Sal and the LSA, and discover that Hector has been creating and selling counterfeit tickets, while hoarding the genuine ones. Olivia leads them all into another trap, and Manny and Sal are taken to Hectors greenhouse to be Sprouted. Manny, however defeats Hector while Sal sacrifices himself to stop Olivia from preventing Manny from gassing them with Sproutella. Manny then recovers the Genuine Tickets, and gives them to there rightful owners, including Meche. Due to many good deeds perform over the four years, Manny is rewarded one too. Manny and Meche then board the Number Nine to go to the Ninth Underworld.