The film was released on October 11, 2013, failing to recoup its budget of $20 million and receiving negative reviews. Critics cited the overuse of plot points, poorly produced CGI, and the 'out-of-place' science fiction elements.
Machete Cortez (Danny Trejo) and Sartana Rivera (Jessica Alba) attempt to capture weapon dealers who have been supplying the Mexican drug cartels. The military men are then all killed by the gangsters, who in turn are wiped out by another intervening party. Its leader murders Sartana while Machete is arrested by corrupt Sheriff Doakes (William Sadler) and Deputy Clebourne (Samuel Davis). Doakes unsuccessfully tries to hang Machete but the President of the US, Rathcock (Charlie Sheen), intervenes. Machete is brought to the White House, where the president offers him US citizenship if he eliminates Marcos Mendez (Demián Bichir), a psychopath who is threatening to fire a nuclear missile at Washington, D.C. if the American government does not intervene to stop the rampant drug cartels in Mexico and the corruption of its government.
Machete agrees and travels to San Antonio, where he meets his handler Blanca Vasquez (Amber Heard), an undercover beauty pageant competitor. She sends him to Acapulco to meet a young woman, Cereza (Vanessa Hudgens), who can lead him to Mendez. Machete finds her in a brothel run by her mother, Madame Desdemona (Sofía Vergara), who attempts to kill Machete before he escapes with Cereza. She takes him to Mendez's associate, Zaror (Marko Zaror), who kills Cereza before taking Machete to Mendez's base of operations.
There, Machete learns that Mendez has wired the missile's launch device to Mendez' heart and triggered its launch in 24 hours. If he dies, the missile fires. After Machete kills Zaror, he also captures Mendez, intending to escort Mendez to US and find a way to disarm the missile. Machete learns that Mendez is an ex-secret agent who tried to expose his corrupt superiors, only to be betrayed and forced to watch his family being tortured. The trauma drove him insane, creating his split personalities and leading him to join forces with the missile's creator.
Shortly thereafter, a hit is put out on them. Machete is targeted by Madame Desdemona and her prostitute assassins, including a shapeshifting hitman called El Camaleón (Lady Gaga), as well as Doakes. Machete and Mendez manage to reach the US and kill Doakes and Clebourne only to be caught by a reborn Zaror and the same mercenaries who killed Sartana. Zaror decapitates Mendez and Machete is riddled with bullets.
Machete wakes up to find himself in a healing tank. He is taken to meet Zaror's benefactor—corrupt businessman, inventor and Star Wars fan Luther Voz (Mel Gibson). He shows Machete Mendez's beating heart, preserved in a jar, and informs him of his plan to manipulate extremists throughout the world to detonate nuclear weapons while planning to escape in a spaceship to rebuild society in space. Machete then escapes with help from Luz (Michelle Rodriguez), who had heard about the hit on Machete. She informs him that the only one who can disarm Mendez's heart is Machete's old enemy, Osiris Amanpour (Tom Savini). Machete contacts Vasquez, who instructs him to meet her at a rendezvous point.
Arriving there, Machete is betrayed and ambushed by Vasquez, who is in league with Voz. As she is escaping into the desert, Machete gives chase and jumps onto the top of her vehicle but falls off after gunfire comes through the roof. Machete is then given a ride by El Camaleón, who tries to kill him one last time. But he escapes and El Camaleón ends up being shot to death by a group of racist rednecks just inside the US border. Machete then reunites with Luz and her group, the Network. They infiltrate a fundraiser at Voz's base of operations, where Voz kills Osiris. Machete realizes Voz was the one who killed Sartana and fights him. He severely burns Voz's face, disfiguring him to the extent that Voz is forced to wear a metallic, silver mask. Meanwhile, Vasquez shoots Luz in her good eye, completely blinding her. Luz kills Vasquez in return but is captured by Voz, frozen in Carbonite and taken aboard his ship.
Machete jumps on the missile as it launches and disarms it in mid-air, while Voz boards the ship and departs with the Zaror clones, his supporters, as well as Luz. The disarmed missile then plunges into the Rio Grande and Machete is rescued by President Rathcock, who asks him to follow Voz into space and kill him. Machete agrees and uses a SpaceX Falcon 9 v1.0 rocket to depart to Voz's Station in Earth's orbit, where he is given a laser machete to start his mission.
On October 9, 2013, Lady Gaga's Vevo released a lyric video for "Aura", a song from her third studio album Artpop, to promote the film.
Machete Kills received negative reviews from critics. Rotten Tomatoes gave the film a rating of 29%, based on 111 reviews, with the critical consensus "While possessed with the same schlocky lunacy as its far superior predecessor, Machete Kills loses the first installment's spark in a less deftly assembled sequel." At Metacritic, which assigns a normalized rating based on reviews from mainstream critics, the film has received a score of 41 out of 100, based on 33 critics, indictating "mixed or average reviews".
Gaga was nominated for a Golden Raspberry Award for Worst Supporting Actress for her work in the film, but lost to Kim Kardashian for Temptation: Confessions of a Marriage Counselor.
At the end of the first film's theatrical version, two sequels are mentioned, Machete Kills and Machete Kills Again. The trailer for the third and final film, Machete Kills Again... In Space, precedes the second film as a "Coming Attraction". In 2015, Trejo told Halloween Daily News that the third film is happening.