In eastern Siberia's Dzhugdzhur Mountains, Dieter Von Cunth (Val Kilmer) and his men take control of a nuclear X-5 warhead from the Russian army after killing all the soldiers escorting the missile during a routine transfer. In Ecuador, Col. Jim Faith (Powers Boothe) and Lt. Dixon Piper (Ryan Phillippe) are searching for former Green Beret, Navy SEAL and Army Ranger MacGruber (Will Forte). MacGruber has served 6 tours in Desert Storm, 4 in Bosnia, 3 each in Angola, Somalia, Mozambique, Nicaragua and Sierra Leone. Recipient of 16 Purple Hearts, 3 Congressional Medals of Honor, 7 Presidential Medals of Bravery, and so on. Finding him meditating in a chapel, they ask him to retrieve the warhead which they say has been moved to US soil. He refuses. That night, MacGruber explodes into a fit of rage, waking from the flashback of Cunth killing his fiance, Casey Fitzpatrick (Maya Rudolph), at their wedding. He accepts the mission. MacGruber has the reputation of being very effective but also causing high collateral damage during his missions.Cunth's team includes Hoss Bender, Constantine Bach (Timothy V. Murphy), Zeke Pleshette (Jasper Cole), and so on. After a heated conversation with Faith and Piper at the Pentagon, MacGruber creates a list and travels to the U.S. to form his team to pursue Cunth. Faith wanted Piper to be MacGruber's 2nd in command, which MacGruber refuses instantly. MacGruber considers Piper to be a rookie with no combat experience.Recruiting all but his long-time friend Vicki St. Elmo (Kristen Wiig) (she refuses as she has a new life now) and Brick Hughes (Big Show) (as he turned gay). MacGruber meets Faith and Piper on the tarmac, while his team (Frank Krover (Chris Jericho), Tut Beemer (Mark Henry), Vernon Freedom (Montel Vontavious Porter), Tug Phelps (The Great Khali), Tanker Lutz (Kane)) is in a van with his homemade C-4 explosives, which explode, killing his entire team. Faith takes MacGruber off the case. MacGruber convinces Piper (he falls on his knees and begs Piper not to kick him off the team) to form a new team, and Vicki arrives at the Pentagon to join them in taking down Cunth.They travel to Cunth's nightclub in Las Vegas to dig some dirt on him. A driver in the parking lot is rude to MacGruber and angers him, so he repeats the license plate number KFBR392 obsessively to remember it. MacGruber gets on stage and announces who he is, his intentions, and where he will be the next day. Piper is angry since all MacGruber achieved is expose himself and his mission, without finding anything about Cunth.Their sting operation has Vicki portraying MacGruber and hanging out on the street as bait. Hoss Bender (Andy Mackenzie), Cunth's henchman, attacks MacGruber and Piper's van, but MacGruber runs down and kills Bender. They check a large amount of cash in his trunk and an appointment later that day in his diary. Piper says that it is obvious that Bender was going to take the cash to the place where the transfer of codes was going to take place. With Vicki disguised as Bender and Piper disguised as MacGruber, the team attempts to break into a warehouse to stop Cunth from getting the rocket operation passwords. MacGruber distracts the guards and Piper kills most of the men but cannot stop the transfer of the pass-codes.Faith tells MacGruber that Cunth is having a charity event that evening and orders him not to show up there. MacGruber completely ignores his orders. At Cunth's charity event MacGruber confronts and threatens him and his guards, who throw him out.MacGruber returns to the Pentagon where Faith reprimands him and takes him off of the case. MacGruber and Piper have beers outside his trailer while MacGruber explains his history with Cunth: MacGruber met him and Casey Fitzpatrick while they were in college; Cunth was engaged to Casey until her affair with MacGruber, who asked her to abort Cunth's baby.MacGruber uses Piper as a human shield to survive an ambush, escaping with Vicki. They believe that Piper was killed in the attack, but he reveals that he was wearing a bulletproof vest. Commending MacGruber on his quick thinking, only to realize that MacGruber wasn't aware of the vest, Piper leaves the team. Seeing MacGruber has been shot in the leg, Vicki takes him back to her house to remove the bullet. She confesses her love to him, admits she is a virgin, and they make love. MacGruber goes to his bride's grave in shame, but her ghost gives her blessing (and has sex with him on her tombstone).Faith calls MacGruber and says that the X-5 has been recovered. He says that Cunth was not involved, and this was the work of Chechen rebels. Faith asks MacGruber to stand down. A senator with gambling debts to Cunth, had given this information to Faith, to relay to MacGruber. MacGruber is not convinced. MacGruber finds and destroys the KFBR392 car after he sees it parked by the side of a street.At Vicki's, MacGruber discovers Cunth has kidnapped her and realizes Cunth plans to blow up Congress during the State of the Union. Cunth calls MacGruber to gloat, MacGruber traces the call and Piper agrees to help on one last mission. Making their way into Cunth's compound, they are captured and taken to Cunth, Vicki and the missile. MacGruber is against using guns, but this time they are pinned down and Piper forces MacGruber to pick up firearms. MacGruber admits that he doesn't know how to use a gun, and Piper gives him a crash course.They pound Cunth and crew into submission and MacGruber handcuffs Cunth to a handrail. MacGruber proposes to Vicki and she accepts. They remove the warhead and guidance system and escape as the missile explodes. Cunth escapes using an ax to chop off his handcuffed hand.Six months later, at MacGruber and Vicki's wedding are his dead team members as ghosts. Mirroring his wedding to Casey, MacGruber spots Cunth with an RPG. He saves Vicki and battles Cunth, throwing him off a cliff behind the altar, shooting him with a machine gun and launching a grenade as he falls, incinerating the corpse, and finally urinating on it from the top of the cliff.