Ex-Federale agent Machete is recruited by the President of the United States for a mission which would be impossible for any mortal man – he must take down a madman revolutionary and an eccentric billionaire arms dealer who has hatched a plan to spread war and anarchy across the planet.

Eight years after the third film, the OSS has become the world's top spy agency, while the Spy Kids department has since become defunct. A retired spy Marissa is thrown back into the action along with her stepchildren when a maniacal Timekeeper attempts to take over the world. In order to save the world, Rebecca and Cecil must team up with their hated stepmother. Carmen and Juni have since also grown up and will provide gadgets to them.

After being set-up and betrayed by the man who hired him to assassinate a Texas Senator, an ex-Federale launches a brutal rampage of revenge against his former boss.