After breaking out of jail in a small Mexican town, a ruthless criminal, nicknamed Azul, ventures off with a guitar case full of weapons and vows revenge on the local drug lord, Moco, who had him arrested in the first place. Meanwhile, a young musician arrives in town carrying his own guitar case which contains his signature guitar. He hopes to find work in the town in order to pursue his dream of becoming a mariachi like his father.
At the Tarasco bar in Mexico, an American man named Buscemi tells the story of how he witnessed a massacre in another bar committed by a Mexican with a guitar case full of guns. The bar's patrons are uninterested until Buscemi mentions the name "Bucho". Meanwhile, El Mariachi has a dream of his El Mariachi, Bucho's underling, who killed his lover dead and shot his left hand. He is awakened by Buscemi, who tells him to continue his search for Bucho at the bar.
El Mariachi is recruited by Central Intelligence Agency agent Sheldon Jeffrey Sands to kill General Emiliano Marquez, a corrupt Mexican Army officer who has been hired by Mexican drug lord Armando Barillo to assassinate the President of Mexico and overthrow the government. Many years before, El Mariachi and his wife Carolina confronted Marquez in a shootout and wounded the general; in retaliation, Marquez took the lives of Carolina and their daughter in an ambush. In addition to El Mariachi, Sands persuades former Federal Bureau of Investigation agent Jorge Ramírez to come out of retirement and kill Barillo, who had murdered his partner Archuleta in the past. Furthermore, AFN operative Ajedrez is assigned by Sands to tail Barillo.