In the breathtaking Dzhugdzhur Mountains of eastern Siberia, a notorious criminal named Dieter Von Cunth and his ruthless crew seize a nuclear X-5 warhead from the hands of the Russian army, leaving no witnesses in their violent wake during a seemingly routine transfer. Meanwhile, in Ecuador, Col. Jim Faith (Powers Boothe) and Lt. Dixon Piper (Ryan Phillippe) are on a desperate mission to find the legendary operative MacGruber, played by Will Forte. A decorated veteran with an array of accolades—16 Purple Hearts and 3 Congressional Medals of Honor—MacGruber is a man of exceptional skill with a history of serving in intense war zones.
When they locate him meditating in a chapel, the duo urges him to assist in recovering the warhead, which they claim has been relocated to U.S. soil. Initially reluctant, the memory of his late fiancée, Casey Fitzpatrick (Maya Rudolph), killed during his wedding by Cunth, ignites a powerful rage within him. Driven by vengeance, he finally accepts the perilous mission.
MacGruber is known for his effectiveness in combat, albeit at the cost of significant collateral damage, which makes him a controversial choice. Cunth's side is bolstered by his crew, including Hoss Bender and Constantine Bach. After a fiery confrontation with Faith and Piper at the Pentagon, MacGruber starts assembling a team to track down Cunth. However, he quickly dismisses Faith's suggestion to have Piper as his second-in-command, deeming him inexperienced.
He attempts to recruit his longtime friend Vicki St. Elmo, but she declines, having found a new path in her life. MacGruber also enlists Brick Hughes, but is again disappointed as Brick has come out as gay. While on the tarmac, disaster strikes—MacGruber’s hastily assembled team meets a fatal end when his homemade explosives detonate unexpectedly.
Despite being taken off the case by Faith, MacGruber, in a moment of heartfelt desperation, pleads with Piper to reconsider and ultimately assembles a new team, with Vicki joining the ranks. Together, they delve into Cunth's nightclub in Las Vegas, where tensions rise after a rude encounter with a driver. Seeking vengeance, MacGruber obsessively notes the license plate number KFBR392. He makes an audacious announcement on stage, revealing his intentions to everyone present, much to Piper's chagrin, as they gain no substantial intel on Cunth.
Their sting operation sees Vicki go undercover, luring Cunth’s crew while MacGruber and Piper attempt to prevent critical information from being exchanged. Unfortunately, they arrive too late to halt the transfer of the warhead pass-codes. Warnings from Faith about Cunth’s impending charity event go unheeded when MacGruber crashes the gathering, leading to a confrontation that results in his expulsion.
Reflecting on the past, MacGruber shares the story of his history with Cunth, revealing their tangled relationships and the lost love for Casey. As they navigate through peril, MacGruber narrowly escapes death while battling his demons. Back at Vicki’s home, she tends to his wounds, and a heartfelt confrontation leads to their intimate connection, providing solace amid chaos.
When it seems the threat is under control, the danger escalates as Cunth kidnaps Vicki, threatening to unleash catastrophe during the State of the Union. United by a sense of purpose, MacGruber and Piper engage in one final mission, braving through Cunth's stronghold to rescue her and confront their adversaries. Mastering the art of gunplay under Piper's guidance, they face off against Cunth and his minions, resulting in a wild showdown. In a moment of triumph, MacGruber handcuffs Cunth, proposes to Vicki, retrieves the nuclear threat, and narrowly escapes as the missile explodes in a fiery blast.
In a twist of fate, months later, MacGruber's wedding is haunted by the memories of fallen companions. As they prepare to say their vows, old wounds are reopened when Cunth reappears, leading to an explosive confrontation reminiscent of their dark past—culminating in a fierce battle that seals Cunth’s fate in a fiery end.
