- 26-year-old Artyom, flees the Metro in Moscow and sets off on a journey through the harsh nuclear winter in Russia.
- Winter of 2035, one year after the Battle of D6, Artyom has grown fed-up of life in the underground, he believes that human life still exists outside of Moscow. He makes regular visits to the radioactive surface with a radio, but receives only static, while returning from one venture he is wounded by mutants, the Spartan Rangers rescue him and take him for an emergency blood-transfusion.
As he's recuperating in hospital, his wife, Anna and father-in-law, Miller, now with prosthetic legs, visit him, the former is worried that Artyom is obsessed and putting himself at senseless risk, the latter scolds him for leaving his post as Spartan numbers are still limited from the battle. Anna makes Artyom promise not to try again, one week later, Artyom is back on the surface with Anna, when they choose to return they spot a train travelling overground, they elect to follow it, a van picks them up, the people inside are Hansa soldiers, along with an old woman and a teen. The two civilians are from outside Moscow proving Artyom right. The van stops and the civilians are taken out to be executed, Artyom intervenes and gets shot and falls into a pit, the bullet was blocked by Hunter's dog tags given to him two years prior. Artyom follows the van from underneath to a base where Artyom meets an elderly engineer, Yermak, he helps Artyom get to Anna, Artyom finds Anna in a console room with a Hansa officer, he and Artyom struggle over a rifle firing on a console which was jamming Moscow communications and suddenly the room is receiving hails from all over Russia and the world, the officer is knocked unconscious and Artyom, Anna and Yermak steal a locomotive which the Spartans try to retake, they recognize the hijackers as their own and Miller is leading them.
Miller was aware of the jamming of communications, a fact he learned only the previous year under absolute secrecy from an anonymous faction known as the Invisible Watchers, the Spartans side with Anna and Artyom, Miller understands they've put themselves in danger with the jammer destroyed and chooses to flee. Once out of Moscow, Miller confesses what he's been told. The war didn't end, many Russian cities were destroyed and NATO occupied what was left, the Russian government played possum to prevent further attacks and they've been silent ever since. They cannot return to Moscow as Hansa would execute them, so they agree to travel to a safe location, there is supposedly a government-controlled bunker at Mount Yamantau. Artyom, Anna, Miller, Yermak, along with Rangers Duke, Damir, Idiot, Sam, Alyosha, Tokarev and Stepan all set out to find life at Yamantau, christening their new train "Aurora".
Their first obstacle is Volga river, occupied by a Luddite cult, they are guarding the bridge leading forward, the cultists fire on the train, damaging a cylinder. Artyom and Anna are sent out to find supplies and a route past, while staying alert for occupying forces, Artyom takes a boat through a church, the preacher, Silantius, warns his people of the invaders, Artyom meets a young girl named Nastya and her mother Katya. Artyom leaves the church and is attacked by the cult's revered Tsar-Fish, a mutated Catfish. Duke drives the beast off with gunfire and Artyom swims to shore, Miller directs Artyom to a crane where an engineer resides, Krest, he can aid the Spartan Rangers in repairing the Aurora. Artyom finds Krest, whom offers the former a pair of binoculars and says he'll join them.
Artyom receives a radio message from Miller, Anna went to investigate a radio tower bearing the Stars and Stripes and search for occupying forces. Artyom falls into an ammo dump and finds Anna without her gas mask, he puts it on hastily and opens the bulkhead doors. Sam and Damir arrive to help her back to the Aurora, Artyom heads back where Stepan has grown attached to Katya and Nastya, he wants to bring them along but Miller refuses saying they haven't enough room. Krest suggests going to a railyard to pick up his railcar and attach a passenger car to the Aurora for extra numbers. Artyom retrieves the railcar and liberates a passenger car from some bandits. Next the Rangers have to seize a merchant tug boat to infiltrate the bridge and open the gate leading out, Artyom and Duke make it to the top of the bridge access with Silantius.
Based on Artyom's actions in the Volga, Duke's fate is determined here. Positive actions such as using the stealthy approach to avoid the cultists and saving some lead to Silantius ordering his followers to stand down and letting the Rangers pass, Duke and Artyom open the gate and jump onto the Aurora. If negative deeds were committed such as killing cultists, Artyom and Duke will be more hostile to Silantius, who will order his followers to fire, Duke will knock him out and be shot, Artyom jumps onto the Aurora alone as the bridge access is destroyed.
Autumn, the next stop is Mount Yamantau, the supposed "Ark" where the Russian government is preparing to rebuild the country, Miller is eager to meet the high command, retrieve a pardon for himself and the Rangers and tell Moscow of the outside. Artyom, Anna, Miller, Krest, Sam and Idiot take Krest's railcar to the bunker, Artyom, Anna and Miller go into the bunker while the others wait until further notice. Inside Miller greets the commanders, they are not government officials, but rather low-level officials and building contractors, their food ran out a long time ago and they have now become cannibals. A doctor takes Anna to examined before cooking due to a cough she's developed, Idiot and Sam rescue Artyom and Miller starting a battle, Artyom goes to find Anna, she's rescued and slits the doctor's throat. Artyom and Anna head to the command center where Miller executes the officers in anger. Idiot is downloading as much data as possible off the consoles at the same time shutting off their rallying hail to prevent further lures, they leave to escape on Krest's railcar with Sam beside them, the pursuing cannibals are sealed in with no communications.
Back on the Aurora a frustrated and livid Miller contemplates all that has happened, no government has survived so there's no chance of amnesty, nor were there any occupying forces. Idiot recommends using satellite imagery to locate non-radioactive zones to retreat to, the satellite data is stored in a bunker in Kazakhstan's Caspian Sea.
Summer, the Aurora makes it to the Caspian, the heat is taking a toll on the passengers, worse, there is little fuel and water. A van drives past them and goes to signal their comrades, Artyom and Damir, a Kazakh-Russian Ranger, investigate and seize the van, a slaver faction, oil diggers, have oppressed the local populace, a lone female sniper is fighting them, her name is Giul. She offers to aid the Spartans in exchange for overthrowing the slaver leader, The Baron. Miller requests Artyom investigate the Caspian - 1 bunker, Artyom descends, Giul and Damir help however they can, keeping the power running from above. Artyom finds the satellite data and returns overground to Miller, Idiot begins examining the images, Miller states they require fuel and water, he's spoken to the Baron who made unacceptable terms, Artyom and Damir are to steal water from an oasis.
Artyom and Damir steal a water truck and take it to the train, Artyom takes a nap on the ride back, when he awakes the slavers are attacking and are defeated easily. The Rangers prepare to move but they still require fuel, Artyom, Damir and Giul are sent to steal a tanker from the Baron's oil rig. Giul sets about setting explosives on the rig, Artyom confronts the Baron in his lair, the Baron's motives were inspired by social-Darwinism, he offers the fuel in exchange for Giul, Damir intervenes starting a shootout with Baron's men. After the battle, Artyom and Damir stop the Baron from dropping Giul over the edge of the rig. Baron tries to choke Artyom with a crowbar and Anna shoots him in the head with a sniper bullet. Giul thanks the Rangers for their efforts and sets off to lead the slaves in revolution.
Based on Artyom's actions in the Caspian, Damir's fate is determined here. Positive actions such as freeing slaves lead to Damir thanking Artyom for what's he done for his people and staying with him out of gratitude. Negative actions such as killing slaves will lead to Damir choosing to stay and join the revolution.
The Aurora leaves the Caspian behind, Miller has studied the maps for a possible safe spot in Taiga, Stepan has proposed to Katya, the marriage is interrupted when Anna coughs up blood, the radiation from the Volga ammo dump has infected her lungs, Katya recommends the fresh air in the Taiga could heal Anna's lungs, if her condition worsens, there's a cure in the city of Novosibirsk.
Autumn, Artyom and Alyosha scout Taiga in the railcar which is suddenly derailed by a rock slide, Artyom is swept under by the current, a woman dives in the water and rescues him. Artyom lost his weapons and has to rely on a crossbow to survive. A faction known as Children of the Forest occupy Taiga, they've split into two group, Pioneers and Pirates, both are hostile to intruders, the former are merciful if the strangers are respectful of the environment. After surviving an encounter with the Master of the Forest, a mutated bear, Artyom meets the woman that saved him, she is Olga, the Pioneer's leader, she directs him to Alyosha's location, she helped him escape and they fell for each other.
Artyom navigates past the Pirate territories in the marshes, eventually meeting up with Alyosha again, he tells of a dam on the verge of collapse and radioactive water behind that'll destroy the valley. Before they can take a zip line back, the Master appears again, Artyom defeats it in combat. Artyom and Alyosha prepare the zip line to catch the Aurora.
Based on Artyom's action's in Taiga, Alyosha's fate is determined here. Positive actions such as sneaking past humans without force will lead to Olga arriving and saying a temporary goodbye to Alyosha, the latter promises to return one day and warns her of the dam, he and Artyom zip down to the train. Negative actions such as killing all humans will lead to Olga being hostile to Alyosha for being associated with Artyom, the two Rangers zip line down, Alyosha receives a crossbow bolt to the shoulder which leaves him wheelchair bound for the rest of the game.
Anna is worsening, the only course is the drug in Novosibirsk. Idiot has studied the maps further and discovered the radiation levels in Novosibirsk are far higher than Moscow, Miller elects himself and Artyom to be the ones to find the drug.
Winter, the dead city of Novosibirsk is so poisonous that only one type of mutant can survive on the surface, Blind Ones. The Rangers go to find a snowplow to fit on the Aurora, Miller and Artyom take the van from the Caspian, yet the path is blocked, so once again, they venture into the dark underground. They encounter a child, a boy named Kirill, the son of Colonel Khlebnikov. He explains the survivors of Novosibirsk metro survived with the aid of an anti-radiation drug, the Radioprotector. He has two samples for Miller and Artyom. Miller takes Kirill with him to find satellite maps in the station bunker which has supposedly found safe surface zones, Artyom heads to the institute containing the cure for Anna.
Artyom endures high-levels of radiation and has to inject his anti-radiation drug into himself to prolong his search, eventually he recovers it and survives a close encounter with a Blind One. Artyom is barely conscious by time Miller finds him, Miller sacrifices his anti-radiation to save Artyom. Miller, Kirill and Artyom take turns driving to the outskirts where the Aurora can pick them up, Miller has died from the radiation and the Rangers rush to save Artyom.
Artyom is bought onboard and is given an urgent blood transfusion from the entire crew.
Two endings occur here.
If 2 or more Rangers, Duke/Damir/Alyosha, are still with the crew, there will be enough blood to save Artyom. During bouts of unconsciousness Artyom will see Miller in his dream. He takes Artyom from a tunnel to the outside, to a hill over looking Lake Baikal, where the Aurora makes its last stop. He understands now that Artyom was right to believe there was life outside the metro, he accepts responsibility for making everyone believe the country was occupied by enemy forces, had he not, Anna wouldn't have gotten ill. He entrusts Artyom to lead the Rangers and for his body to be buried at the hill.
Artyom recovers, Miller is buried and the Rangers elect Artyom as their new leader. Artyom's intends to fulfill Miller's original goal helping all people, to rebuild the world.
If only one Ranger or none can provide additional blood for Artyom, he dies from the radiation. Artyom will be in a tunnel and the Aurora will run him over, he finds himself aboard a ruined version of the train, ghosts of his past appear, Eugenie, his childhood friend, Bourbon, the smuggler and Khan, the mystic. Miller is there, telling Artyom to step off at the station, Artyom departs and approaches a mail box containing a postcard of Lake Baikal, where the Rangers are now.
Miller and Artyom are buried at Lake Baikal, Anna will be mourning them and the Rangers hold a 21-gun salute in their honor.
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