Aaron Cross, played by Jeremy Renner, is a participant in Operation Outcome, a covert U.S. Defense Department black-ops initiative designed to enhance the mental and physical capabilities of its operatives using performance-enhancing pills known as "Chems." Tasked with a training mission in the harsh wilderness of Alaska, Cross must navigate treacherous terrain to reach a secluded cabin. There, he encounters an exiled operative, Number Three, portrayed by Oscar Isaac, who shares that Cross has shattered the previous mission record by two days.
As events unfold, the existence of the Blackbriar and Treadstone programs comes to light, prompting a wide-ranging investigation by the FBI and the U.S. Senate Select Committee on Intelligence. The inquiry draws in key figures, including CIA Director Ezra Kramer, played by Scott Glenn, Deputy Director Pamela Landy, portrayed by Joan Allen, and Blackbriar supervisor Noah Vosen, played by David Strathairn. To counteract the fallout, Kramer recruits the retired U.S. Air Force Colonel Eric Byer, played by Edward Norton, who discovers incriminating footage online involving the main researchers of Treadstone and Outcome, prompting him to launch a drastic campaign against Outcome's agents to protect their classified operations.
In a shocking turn of events, Byer orders an unmanned drone to attack the cabin, determined to eliminate both Number Three and Cross. Just as the missile strikes, Cross narrowly escapes and employs quick thinking to elude the drones by utilizing a thermal blanket and improvised tactics. Understanding that he is now a target for elimination, Cross goes to extreme lengths, including removing a tracking device from his body and feeding it to a wolf, demonstrating his resourcefulness and survival instinct.
With his former allies turning against him, including the planned assassination of other Outcome assets through lethal means, and the mysterious heart attack of Dr. Albert Hirsch, portrayed by Albert Finney, Cross finds a last hope in Dr. Marta Shearing, played by Rachel Weisz, the sole survivor of a recent attack on the research lab. Cross's dwindling supplies of Chems lead him on a gripping quest back to the lab for more.
When CIA assassins threaten Shearing's life, Cross bravely intervenes, forging an alliance that offers him his only shot at survival. Throughout their harrowing journey, she discloses that Cross has unknowingly undergone genetic modifications that will allow him to retain some of his enhanced abilities without constant drug intake, but he still needs to replenish his blue Chems for cognitive enhancement.
Their desperate run leads them to Manila, where they aim to secure the viral "stems" that produce the Chems, thus ensuring Cross can revert to a state of being free from dependence on the drugs. However, Byer, ever the hunter, is hot on their trail, culminating in a series of high-stakes confrontations, including a brutal chase where Cross and Shearing narrowly escape multiple threats.
As they navigate the dangers of both law enforcement and super-soldiers like LARX-03, played by Louis Ozawa, they manage to evade their pursuers through audacity and quick wit. The film concludes with Cross and Shearing making their way to freedom on a boat, symbolizing a new beginning amid the chaos, having salvaged hope from their relentless fight for survival against the odds.
