Machete (Danny Trejo) is a renegade former "Mexican Federale". He roams the cities, towns, and streets of Texas looking for work after a shakedown from a drug lord called Torrez (Steven Segal).Machete has a run-in with Michael Benz (Jeff Fahey), a local businessman and spin doctor, who tells Machete that McLaughlin (Robert De Niro), a corrupt senator, is sending hundreds of illegal immigrants out of the country and that he must be killed. Benz offers Machete $150,000 to kill McLaughlin who quickly accepts the murder contract out of greed for the money.
Attempting to assassinate the senator at a political rally, Machete is double-crossed and is shot in the shoulder by Benz's henchmen whom are soon revealed to be in league with Senator McLaughlin who orchestrated the entire attempted assassination with Benz as part of a false flag operation to gain widespread public support for McLaughlin's harsh anti-immigration laws by setting up Machete as the patsy to make it appear that an outlaw illegal Mexican immigrant tried to assassinate the senator.
Now on the run from the law and being tracked not only by a ruthless henchwoman hired by Torrez, but Machete is also tracked down by Sartana (Jessica Alba), a persistent U.S. Immigration and Customs Enforcement agent with a special interest in the blade slinger.
Machete goes after Benz and his men, as well as Senator McLaughlin, with the help of his only three allies; his "holy" Federal-turned-priest brother Padre (Cheech Marion) with a thing for pump-action shotguns; a saucy meat cleaver-wielding taco slinger named Luz (Michelle Rodriguez); and Benz socialite daughter April (Lindsey Lohan), whom Machete kidnaps and who soon develops a fascination for the blade-wielding fugitive since April has a penchant for guns. Machete rallies a group of illegal migrants together, and they all begin to hunt the people who double crossed him.