The game starts with a quote from Marco Polo, “I did not tell half of what I saw, for I knew i would not be believed.” The main story is of the voyage home of Marco Polo from China in 1292. He spent almost 20 years in the court of the Mongol Emperor Kublai Khan, Marco Polo left with fourteen ships and over six hundred passengers. He arrived in Persia a year and half later, only one ship and eighteen passengers remaining. Polo kept to himself of everything that had happened with the lost ships and people.
Nathan ‘Nate’ Drake awakes hanging off a cliff in a train with a bloody wound in his stomach. With flashback the story explains that Harry Flynn and his old girlfriend Chloe Frazer approached him with a job to steal the a Mongolian oil lamp from an Istanbul museum. Drake accepts the job finding out that the lamp may contain a map from Marco Polo’s lost fleet. Flynn and Drake steal the lamp and discover a map showing that the lost fleet had been transporting the Cintamani stone from the mythical city of Shambhala (or Shangri-La). Flynn steals the map and double crosses Drake getting him arrested and jailed for three months. Chloe, which claims to have no idea that Flynn was going to double cross Drake bails him out of jail along with Victor ‘Sully’ Sullivan.
Nate and Sully follow Flynn and his Boss Zoran Lazarevic, a war criminal from Serbia, which was thought to be dead. Chloe now works as a mole in Lazarevic’s camp discovers that the Cintamani Stone was never on the fleet. They find a tomb that contained the bodies of Marco Polo’s fleet as well as a Tibetan phurba, and a letter from Marco Polo stating to go to the Kathmandu, Nepal in a temple for the next clue. Flynn and his men find the tomb and takes the letter, but Sully and Nate escape by jumping off a cliff into a river. Sully backs out to go to Nepal but Chloe decides to accompany Drake. When arriving they find that Lazarevic demolished the entire city looking for the right temple. After noticing that a symbol on the phurba marks the way to the right temple they survey the area looking for the matching symbol.
While on their journey in Nepal they run into Elena Fisher and her cameraman Jeff whom are tracking down Lazarevic to prove that he is alive. The four of them reach the temple but Elena is puzzled as to why Lazarevic would even need the money. Each group departs and Drake discovers that the stone and Shambhala are in the Himalayas. When they are about to leave, they get ambushed and Drake runs out to help Elena and Jeff but discovers that Jeff had been shot by one of Lazarevic’s men. Chloe insists on leaving him but Drake and Elena push on to help him until they are caught by Flynn and Lazarevic. Chloe pulls her gun to Drake and pretending to still be on their side, Flynn takes Chloe to the train yard and Lazarevic kills Jeff. Lazarevic takes the map and tells Flynn to kill Drake and Elena, but when he tries to get her up Elena punches him and Drake punches the guard and they both get away.
Elena has trouble helping Chloe because of her betrayal, but in the end decides to help. They both steal a jeep driven by Elena to catch up with the train, and Drake jumps aboard. He then fights soldiers, a helicopter (twice) and fights the Lt. Darza, who has the phurba dagger. Drake beats him and gets the dagger back. Darza regains consciousness and tries to kill Drake but gets shot by Chloe. They both argue because Chloe is upset that Drake helped Elenea and Jeff then Flynn arrives and shoots Drake in the stomach. Chloe jumps in front of Flynn giving Drake the opportunity to flee. Drake eventually gets cornered by Flynn’s soldiers, having nothing else to do Drake shoots a pile of propane tanks killing all the men but splitting the train and sending Drake’s half off the cliff.
Now the game returns where it started with Drake lying in the train. He narrowly escapes and travels through a snowstorm where he finds the phurba and falls unconscious. He awakes in a Tibetan village, there he finds Elena and is introduced to Karl Schafer. He tells Nate that the phurba is the key to Shambhala but Drake is uninterested in the journey. Schafer decides to convince Drake by sending him and the village leader Tenzin to the remains of his expedition 70 years ago, in the search for Shambhala and the stone. After dealing with yeti like creatures they both arrive at the location and discover that Schafer and his men were SS members on an Ahnenerbe expedition and that he killed them to protect the world from the power of the stone. They return to the village and find Lazarevic’s men attacking the village because of Drake and Elena. Drake and Tenzin fight for the village and even defeat a tank.
Drake and Elena discover that Schafer had been kidnapped along with the phurba. They follow Lazarevic’s convoy which led to an abandoned monastery and got blown off a cliff, but eventually gaining entrance by the mountains which they then infiltrated. They find Schafer mortally wound and he tells Drake to find the Cintamani stone and destroy it. He then dies and Drake decides to carry on and find the stone. Elena figures if they split up they’ll find the entrance faster, which he agrees to do.
Drake finds Chloe and she surrenders the phurba after he tells her he’s taking down Lazarevic. Drake then reunites with Elena and they beat Lazarevic and using the phurba to unlock the passage to Shambhala, but Lazarevic’s corner’s them and makes Drake chose between Chloe and Elena, since Chloe’s cover was blown by Flynn. Nate agrees to go with Flynn to open the gate. When they open the gate they are attacked by the yeti like creatures. Lazarevic kills them and it is now discovered that they really are human guardians of Shambhala powered by the Cintanami stone and dressed like yeti’s to scare away anyone that gets too close to the city. Lazarevic is now about to kill Drake and Elena but gets interrupted by another wave of the guardians, which allowed for Drake, Elena and Chloe to escape.
Inside of Shambhala they make their way to the central temple, where Drake now figures out that the Cintanami stone is really a giant amber of petrified blue resin embedded in a giant tree of life. The real treasure of the Cintanami stone is if the drinker ingested the resign they would become nearly invincible. Before they encounter Lazarevic, a wounded Flynn arrives and detonates a grenade killing himself and wounded Elena. Chloe decides to look after Elena as Drake leaves to fight Lazarevic, but on arriving Lazarevic had just drank the tree sap which makes him nearly indestructible and heals all his wounds and scars. Drake manages to beat Lazarevic by detonating the explosive sap around him, the guardians then arrive, beating him to death. Drake reunites with Chloe and Elena as they leave a series of explosions completely destroys Shambhala.
When they get back to the village Chloe ask Drake if he loves Elena and he does not deny it. Chloe leaves and Sully brings a recovering Elena over to him. Sully chases after Chloe, while Drake and Elena pay their respect to Schafer’s grave. They have a kiss and walk over to the edge of cliff as the sun set behind the mountains.