Make people like Machete (Danny Trejo), whatever will she do as long as it can make money, even if that meant he had to kill. Unfortunately this time Machete victim was taken as a pawn in a conspiracy involving high-level officials in Texas.

Machete Cortez is a former Mexican Federal Police who fled from his unit. Had no steady job, Machete finally willing to accept any job as long as can make money. At that moment Machete met Michael Booth (Jeff Fahey), a businessman who offered a job Machete. Michael McLaughlin told Machete to kill Senator (Robert De Niro) who reportedly was the corrupt politicians who hate immigrants from Mexico.

With the lucrative pay, Machete is accepting this offer. When Machete had planned execution, all of a sudden there are other people who turned out to also target the lives of Machete. Apparently Machete being set up to make it appear as if there were illegal immigrants who tried to kill Senator McLauglin. Machete fortunately managed to escape and is now a fugitive minions Senator McLauglin. At the same time, there was an immigration officer named Santana Rivera (Jessica Alba) is assigned to catch the Machete.

With the help of She (Michelle Rodriguez), Machete then recruited Padre (Cheech Marin) to avenge him in Booth. The three were later abducted April (Lindsay Lohan), daughter of Michael Booth who was addicted to drugs.