Set around three years after the events of the first 'Sicario' film, this sequel opens near the US-Mexico border in Texas. A team of operatives catch a man trying to get across the border. He is cornered by the other men until he pulls out a detonator and blows himself up.In Kansas City, Missouri, a group of terrorists perform suicide-bombings inside a department store, killing a number of civilians, including children. This raises the level of concern that terrorists are being smuggled into the United States from Mexico.CIA Agent Matt Graver (Josh Brolin) is brought in to meet with a suspected terrorist smuggler named Bashiir (Faysal Ahmed), whom Matt believes brought in the guys responsible for the store bombing. Matt demands Bashiir to give up the names of his employers, or an airstrike will take out his home with his family inside. Bashiir fails to give up any information, and Matt forces him to watch as the airstrike kills his brother.Somewhere in a Texas border town, we meet a young Mexican boy named Miguel Hernandez (Elijah Rodriguez), who skips school and joins his friend Hector (David Castaneda) as they hang out to smoke weed near the border. Hector's friends, who are in league with the cartel, are hanging out nearby. Hector offers Miguel employment with the cartel, promising a lot of money if he helps out. Miguel reluctantly agrees to join.In Washington DC, Matt is brought in to the Department of Homeland Security by a government official named Cynthia Foards (Catherine Keener) to meet with Secretary of Defense James Riley (Matthew Modine) to discuss a new mission. They want to start a war between Mexican cartels in order to put an end to the suspected terrorist smuggling. The plan is to go against the Matamoras Cartel, as well as their rival, led by kingpin Carlos Reyes. Matt is instructed to kidnap Reyes's youngest child. Matt agrees on the condition that he works dirty, which is exactly what Riley and his men want from him.Matt goes to find former 'sicario' Alejandro Gillick (Benicio Del Toro), who is now living in semi-retirement in Bogota, Columbia, telling him that they are turning him as loose as he can get with a new 'sicario' mission. With that, they travel to the USA and make their way across the border and find a group of men working for the Matamoras Cartel, including a top lawyer named Diaz.In Mexico City, Alejandro and his team of operatives shoot the other men as Alejandro goes after Diaz. He shoots him twice to bring him down, and he tosses Diaz a pair of glasses to look upon his killer. Alejandro removes his mask, bids Diaz farewell, and unloads his gun into him.At a private school, we meet Isabel (Isabela Moner), the young teenage daughter of Reyes. She is fighting another girl who scratches her face, prompting Isabel to deck her hard in the face. When they see the headmaster, Isabel says the other girl called her a "narco whore" and attacked her first. Isabel dares the headmaster to expel her, but he doesn't. As she is being escorted home by bodyguards, their van is ambushed by an explosion, followed by another car crashing into them. Alejandro, pretending to be a Matamoras member, kills the guards and kidnaps Isabel.Alejandro brings Isabel to a house in Texas where they stage a fake rescue to escort her back to Mexico. On their way back, Alejandro, Matt, Steve Forsing (Jeffrey Donovan), and Isabel's van are ambushed by Mexican Federal Police, who begin firing upon the Americans' convoy with bullets and RPG's. Isabel makes it out of the convoy and hides while the other men fire back. The remaining Mexican policemen appear to beg for mercy until one of them draws their weapons on the other agents, forcing them to return fire and kill them all. Matt and his team are forced to return back across the border while Alejandro volunteers to stay behind to find Isabel.Back in the States, Cynthia confronts Matt over their retaliation in the ambush because now the Mexican government has become aware of their operation. Additionally, the Kansas City bombing wasn't a result of the cartels, but from an unrelated group of terrorists. The situation has gotten so bad that the President of the USA has decided to shut their operation down over fears of being impeached, but Matt argues that they did what they had to do.Meanwhile, Isabel goes on the run and is caught by a lone agent. Before he can take her away, Alejandro blows his brains out. He personally escorts Isabel away, saying he will not hurt her. He reveals to her that he is one of her father's enemies. They find a deaf man named Angel (Bruno Bichir), and Alejandro is able to sign to him that he is not dangerous and that he only needs food and water for him and Isabel. Angel asks Alejandro how he knows how to sign, and he says he learned it from his deceased daughter. Later that night, Isabel realizes she knows about Alejandro being the lawyer whose family was murdered. He confirms that it was her father who ordered the hit that was carried out by Fausto Alarcon.Alejandro gets in touch with Matt, who orders Alejandro to kill Isabel since she was a witness to the ambush firefight. Alejandro refuses, officially going rogue. This leads Matt to order a team to go after him and Isabel.Meanwhile in Mexico, Miguel and his fellow gang members are initiating an operation in which they will start smuggling Mexicans over the border.Alejandro decides he must smuggle Isabel across the border so that the U.S. agents can't touch her. She cuts her hair and pretends her name is Carina. They board a bus with other Mexicans being smuggled, but the two of them are found by a gang leader who thinks he can sell Isabel back to her father for a large reward. The gang members pull the two out of the bus after binding and gagging them. The leader orders a young man named Jose (Tenzin Marco-Taylor) to execute Alejandro, but he can't bring himself to do so, and Jose is shot in the head. Miguel is then ordered to come up and do the task. He shoots Alejandro through the jaw, seemingly killing him. The gang members leave while Matt and Steve watch from the sky and see Alejandro's body. Steve says he is glad they did not have to do that themselves. Matt tells Steve it is time to clean the place up.The gang drives away, congratulating Miguel for his work. However, he decides he wants no part in their world, and he hops out of the van. Matt and his team then come across the gang and shoot them all dead. Matt recovers Isabel and decides to bring her back to the States so she can be put in witness protection.Alejandro turns out to have survived his gunshot, despite losing a lot of blood. He frees himself by cutting the tape off using Jose's belt before heading off and finding the gang's van and their stash of weapons. As he drives away, he is spotted by two other gang members that try to shoot him, but he tosses a grenade in their car to blow them up. Alejandro then drives slowly off-road and crashes into a post from blood loss.One year later in Texas, we see Miguel (now sporting a number of tattoos on his body) as he walks into a shopping mall to his job in the food court. He finds Alejandro in the backroom, with his face wounds now having healed. Alejandro decides to teach Miguel the ways of the sicario (hitman).