El Mariachi, portrayed by Antonio Banderas, finds himself pulled into a dangerous mission when CIA officer Sheldon Jeffrey Sands recruits him to eliminate the corrupt General Emiliano Marquez, a high-ranking officer in the Mexican Army. With Marquez being a puppet for the ruthless drug lord Armando Barillo, who is scheming to assassinate the President of Mexico during a tumultuous period in Culiacan, the stakes have never been higher.
As unrest brews, the President (played by Pedro Armendariz, Jr.) courageously calls upon the people of Culiacan to unite against the growing threat posed by Barillo's criminal empire. According to Nicholas, the President's advisor, Barillo has a reputation as a folk hero, having seemingly improved the lives of many by distributing land. Yet, the President stands firm, knowing the truth of Barillo’s violent past. With faith in the people's discernment, he believes they will not fall for the facade.
Sands learns of El Mariachi’s reputation and knows he must take immediate action to recruit him, despite the fact that every cartel in Mexico seeks to have him dead. Meanwhile, Barillo’s machinations lead him to find a lookalike for an elaborate plan involving facial reconstruction surgery; he aims to completely erase his identity and have his doppelgänger assume his position.
Bellini, a friend of Sands, recounts the history of El Mariachi, recalling a time when he and his wife, Carolina, were nearly killed by Marquez during a tragic shootout. Carolina, originally allied with Marquez, ultimately betrayed him to save El Mariachi, resulting in a relentless vendetta after Marquez ambushed and murdered both Carolina and their daughter. This harrowing loss fuels El Mariachi's determination to hunt down Marquez mercilessly.
Sands goes to great lengths, even paying Bellini $10,000 for El Mariachi's contact information, leading to a meeting where Sands tests El Mariachi's survival skills by sending assassins after him. Alongside his mission, Sands persuades Jorge Ramirez, a former FBI agent once tormented by Barillo’s actions, to join the fight against the drug lord responsible for his partner's death.
Meanwhile, Ajedrez is another operative working under Sands, tasked with tracking Barillo but struggling against the limitations placed on her as a woman in the police force. As Sands collaborates with Nicholas to eliminate the President, he plays a dangerous game, wanting Marquez dead just after the President meets his end.
Interwoven in this narrative are other characters like Billy Chambers, an American fugitive entangled with Barillo, who faces moral dilemmas and seeks a way out of his corrupt existence. Chambers cooperates with Ramirez in hopes of taking down Barillo, leading to a series of deadly confrontations where loyalties and schemes implode.
As events unfold, Sands soon finds himself in turmoil; his plans unravel as he gets captured by Barillo, suffering a fate worse than death. In a chaotic climax during the Day of the Dead celebrations, El Mariachi steps up, defying Sands’ orders, and intervenes to protect the President.
With gunfire erupting in the presidential palace, a fierce showdown occurs. El Mariachi finally faces Marquez again, delivering a long-awaited retribution for his family’s death. In the end, after a series of betrayals and confrontations, El Mariachi and Ramirez manage to take down Barillo and Ajedrez, reclaiming their honor.
Against all odds, El Mariachi chooses to give his share of the spoils back to his village, symbolizing hope as he strides into the sunset, forever marked by the battles fought for justice.
