She kills Vasquez with her own tiara. Machete disarms the missile, but Voz takes She and they go into space on his rocket. The President puts Machete on another rocket and orders him to get Voz, setting up the events of the third movie.
The movie begins with a trailer for the next movie in the series, Machete Kills Again...In Space.
ICE Agents Machete (Danny Trejo) and Sartana (Jessica Alba) are at the Arizona/Mexico border attempting to stop the sale of weapons from a rogue military outfit to a drug cartel. The cartel shows up and kills all of the soldiers, but then a masked group shows up and they, along with Machete, kill the cartel members. The group leader, wearing a luchador mask, kills Sartana and wounds Machete. The local corrupt Sheriff Doakes (William Sadler) and Deputy Clebourne attempt to lynch Machete, but a phone call from the US President interrupts them, and they are ordered to cut him down and send him to Washington. In the White House, President Rathcock (Charlie Sheen, credited by his birth name Carlos Estevez) orders Machete to go to Mexico to kill Marcos Mendez (Demian Bichir), a psychopath who has a missile pointed at Washington, and will launch it unless the USA wipes out all of the cartels. If successful, Machete will have his criminal record erased and be given US citizenship.
Machete accepts the assignment and travels to San Antonio to meet his handler Blanca Vasquez (Amber Heard), who is undercover as a beauty contestant. She sends him to Acapulco, where he meets up with Cereza (Vanessa Hudgens), a prostitute who can lead him to Mendez. Her bordello is run by her mother Madame Desdemona (Sofia Vergara), who attempts to kill Machete before he and Cereza escape. She agrees to take him to meet Mendez, but to get to him they have to go through his associate Zaror. On the way to his base, Cereza tells Machete that Mendez has a split personality; one loving and one deadly, and no one knows which one will appear that day. Afterwards, Zaror kills Cereza on Mendez's orders. At the base, Machete meets Mendez, and sees that he has attached the trigger to the missile directly to his heart, and if it stops, the missile will launch immediately. Mendez says the only person who can disarm it is the inventor in the US, then he activates the trigger's fail-safe, which will launch the missile in 24 hours. Machete is able to kill all of Mendez's men, including Zaror, and they use a helicopter to escape.
Following the escape, a bounty is read over Mexican radio, placing it on the heads of Mendez and Machete, and several people, including Doakes and Clebourne, hear it. Another person to hear it is a hitman known as The Chameleon (Walton Goggins). After completing another hit, he takes off his mask, and it reveals another face (Cuba Gooding, Jr.), thus the name Chameleon. After killing a pair of tourists to steal their car, that face comes off and The Chameleon is now a woman (Lady Gaga). During their drive to the border, Mendez (in his normal persona) tells Machete he was a secret agent working undercover to destroy the cartels from within. One of his own men betrayed him, and with his cover blown, watched his family get murdered. That set off the killer persona, and he has been going back and forth ever since. He believes that if the US won't help clean up their mess, he will send a mess back to Washington in the form of a missile.
With everyone from The Chameleon to corrupt Federales to an avenging Desdemona trying to kill them, Machete and Mendez finally make it over the border, only to be met by Doakes and Clebourne. Machete and Mendez, back in his killer mentality, kill the duo. Mendez then sees and welcomes the group that killed Sartana, led by a still alive Zaror. He promptly decapitates Mendez and the group shoot Machete multiple times.
Machete wakes up in a healing tank, and then meets Luther Voz (Mel Gibson), the man who invented Mendez's trigger and gave him the missile. Mendez's heart was cut out of his body, so the trigger is still active, and it has about 6 hours left on the fail-safe. Voz then takes Machete around his factory and reveals his grand plan. He built a space station and plans on filling it with people who want to escape the impending end of the world on his rocket and rebuild society. The end will come when the world's other "Mendezs" launch their missiles, bringing on armageddon. Voz will also need an army to protect themselves, and that is when the clone army of Zarors comes in and attacks Machete. He is able to kill them easily with a futuristic machete knife, and Voz then tells Machete he wants to hire him to be the mold for the next generation of clones. Machete says no, and then escapes the factory, leaving behind Mendez's heart.
During his escape, Machete is picked up by She (Michelle Rodriguez), who also heard the message about the bounty and has been tracking him ever since. Her network has grown larger, and Machete asks her if she knows anyone who can disarm a bomb. She tells him the only person who can do it is Osiris, the man who killed Machete's brother in the first movie. With no other choice, Machete calls Vasquez and they arrange a meeting for a mission debrief. It's a trap, as Machete learns that she is working for Voz. He chases her out into the desert, but she gets away. While walking back to She's base, Machete is picked up by a trucker (Antonio Banderas), who is actually The Chameleon with yet another new face. He is making Machete dig is own grave, but he comes across an underground tunnel and goes into it. The Chameleon gives chase, but comes out of the tunnel and into the gunbarrels of several rednecks, who kill him thinking he is an illegal alien. Machete climbs out of the tunnel and makes it back to the base.
With the entire network ready to take out Voz, they and Machete infiltrate his compound as everyone, including Vasquez, is about to board the rocket. While She and the network take out the guards, Machete and Osiris attempt to disarm the trigger. But Voz shoots the heart, causing the missile to launch in 5 minutes, then kills Osiris. As he is chasing Voz, Machete comes across several masks, including a luchador mask, revealing Voz as Sartana's killer. In the ensuing fight, Machete is able to severely burn Voz's face, which he covers with a silver mask. Meanwhile, Vasquez shoots She in her one good eye, leaving her permanently blind. Despite that, She is still able to fight Vasquez, and she kills her with her own tiara. But Voz then freezes She in carbonite (he earlier mentioned he is a Star Wars fan) and takes her, and the remaining members of the network, onto the rocket and launches it. With the missile about to launch, Machete climbs onto it and attempts to disarm it, even after it launches. Using his machete, he tears out the wires, causing the missile to crash into the Rio Grande without detonating.
As he is exiting the river, Machete is met by the President, who tells him that the other missiles have been disarmed. Machete tells him that Voz is now in space, so the President asks if he wants to go into space to get him, and Machete enthusiastically says yes. The movie ends with Astronaut Machete boarding a Space X rocket and as it launches, the preview from the beginning of the movie plays again, saying that Machete, as well as Voz, She, and The Chameleon, will return in Machete Kills Again...In Space.