Sometime in the near future, paraplegic prison inmate Matt Mills meets "The Board" of Satoshi-Telefair Industries, who thank him for joining the Program. Under pressure and with a promise to make him walk again, Mills agrees to volunteer. He is injected with a synthetic nanomaterial and suffocated, only to wake up with restored use of his legs, yet alone in a steel cell in the first spoke of an experimental apparatus - The Wheel. A series of assailants inflict a multitude of damage to Mills' body and torment his mind, yet the synthetic nanomaterial not only restores his damaged organs, it re-engineers his strength. The experiment might be designed to kill, but Mills is determined to survive - and get back to his daughter before The Board finds her first.

因为一次意外，身经百战的杀手弗兰克（摩根·弗里曼 Morgan Freeman 饰）失手被抓，然而，在被押解的途中，弗兰克一行人竟然遭到了同伙的袭击，重伤的法警和弗兰克一同掉入了河中不知去向。
　　雷（约翰·库萨克 John Cusack 饰）带着儿子克里斯（Jamie Anderson 饰）准备进行一场有趣的野营，没想到河流中竟然飘来两名男子，正是法警与弗兰克两人。法警告诉雷，弗兰克是一名重刑犯，他嘱咐雷务必要将弗兰克送至法院。而弗兰克是一个有原则的杀手，他的原则就是无论如何一定要将目标置于死地。一边是执着正义的雷，一边是老奸巨猾的弗兰克，在这两人之间，一场没有硝烟的战争拉开了序幕。

超级病毒“金美拉”和抗生素在运送途中，被恐怖组织头目Sean Ambrose（ Dougray Scott 饰）盗走，Ethan Hunt（Tom Cruise 饰）率领他的IMF小组接受中情局的任务，找回病毒。 这次，Ethan Hunt找到了女飞贼Nyah Nordoff-Hall（Thandie Newton 饰）搭档，后者是Sean Ambrose的前女友。Ethan Hunt在获取Nyah信任的同时，二人也暗生情愫。 但是，为了完成任务，Ethan Hunt不得不安排Nyah回到Sean Ambrose身边卧底。 Nyah终于打探出病毒所在的药厂，接获情报的Ethan Hunt前往药厂准备销毁病毒；另一边，Sean Ambrose已经察觉出了Nyah回到自己身边的真正目的，组织人马在药厂等待Ethan Hunt自投罗网。 激烈的搏斗中，Nyah为了帮助Ethan Hunt完成任务，将病毒注入了自己体内，只有在20个小时之内将抗生素注入Nyah体内，才能挽救她的性命，Ethan Hunt又将面临不可能的任务。