Far out into the ocean the game begins with Nathan “Nate” Drake recovering a coffin of his descendant Sir Francis, an Elizabethan explorer, from the bottom of the ocean floor. He inherited a ring with the coordinates to find this set location. The expedition is funded by Elena Fisher, which is there to document the discovery. When they open the coffin they find out that it’s empty and all that’s in it is a diary written by Sir Francis which shows that he faked his own death. A band of pirates then appear and begin to attack Nate, Ellena and the boat, but they were quickly rescued by Drake’s friend and partner Victor “ Sully” Sullivan.
When returning to shore Nate and Sully examine the diary and discovered some information pointing to the location of El Dorado, a mythic city of gold said to be located in the Amazon. Worried that Elena would document the discovery and bring on competition for them, they decide to ditch her and travel to Amazon. When arriving they find ruins of an ancient South american civilization, and they come to a conclusion that El Dorado in not a city of gold but a large golden statue that was removed by the Spaniards long ago. Searching further, they discovered a long abandoned German U-boat stuck in a river. The entire crew appeared to be mauled to death and they discovered Spanish gold coins with an unknown mint stamp on it, and the missing page to the diary Nate discovered from Sir Francis coffin which points to a southern tropic island where the Spaniards had possibly taken the statue.
While exiting the submarine Nate runs into Gabriel Roman, a competitive treasure hunter that hired mercenaries led by Atoq Navarro, Roman’s lieutenant and an archaeologist with much knowledge regarding the statue. Roman learns of their quest for El Dorado when Sully owed Roman money and explained to him he was onto something big and was going to pay him back afterwards. Nate refuses to help Roman and he shoots Sully in the chest. Nate struggles with Navarro then the submarine explodes from a torpedo that Nate accidentally activated. Using this as a diversion Nate escapes into the jungle and also saves Elena in the process. The two fly off in Sully’s plane and head to the Pacific island from the diary.
As they approach the island their plane gets shot down and they both get separated. Nate makes his way into the fort where he finds Elena’s parachute but is unable to find her. He continues his way into the tower when he finds a message from Sir Francis stating that he went to the fort tower. When arriving Nate is captured by a pirate who is revealed to be Eddy Raja, an old rival of his. Eddie tries to get Nate to help him find the treasure but Elena ends up breaking Nate out. the two make their way to a long abandoned port city and discovers through a log book in a custom house that the statue was moved more inland. Elena then spots Sully working with Roman and Navarro, the two decide to follow them to the monastery. Elena loses her camera to save herself and the two find hidden passages and rescues Sully, where he then explains how Nate’s diary blocked the bullet and saved his life, he then decided to play along and pretend to aid the enemy.
Nate makes his way through a maze of underground tunnels and eavesdrop on Roman, Navarro and Eddy. Roman hired Eddy for protection on the island and Eddy keeps talking about a curse that is killing his men. Roman ignores this and Eddy gets angry and pulls his gun to Roman, Navarro stops Eddy and he quickly storms off upset and Nate wonders if he’s the only one against Roman and his team.
Nate makes his way through more of the tunnels and manages to find an empty treasure vault. In the vault lies Sir Francis dead body. Seeing the seemingly fruitless quest of Sir Francis, an upset Nate leaves the ring behind with Drake’s body. Before leaving they encounter a very frightened Eddy running for his life by these mutated human like creatures, with incredible strength and speed. Eddy and Nate briefly fight off the creatures but Eddy gets killed in the process. Nate and Elena escape and made their way into an abandoned German submarine base, but in order to press on Nate needs to turn on the power to the base. During his exploration Nate discovers that the Germans seeked the statue during World War II, but just like the Spaniards their fate ended up the same and they turned into the mutated creatures. Sir Francis discovering what the statue was capable of, was actually trying to keep the statue on the island making sure no one was able to get off before he was killed by the creatures.
Nate makes his way back to Elena but discovers she’s been captured by Roman and Navarro. As Nate follows them he meets up with Sully and they fight their way to Roman which has now found the statue. They both get captured at gunpoint and are now standing in front of the statue watching as Navarro encourages Roman to open it. When Roman opens the statue he inhales the mutagenic dust that comes out from the mummy that lies within. He then begins to change into the mutated creatures. The mutated Roman now tries to attack Navarro but he’s shot and killed. His plan all along was to steal the statue and sell the mutagen as a weapon to the highest bidder. He then lifts the statue out by helicopter and takes Elena captive while his men are killed by the mutated creatures. Nate then jumps onto the net holding the statue just as the helicopter leaves, the gunman notices Nate on the net and tries to shoot him but Elena kicks him out of the helicopter. As the gunman fell out of the helicopter he widely fired his M4 and kills the pilot, sending the helicopter crashing into Roman’s freighter.
Nate makes his way through the mercenaries and prevails in a fist fight with Navarro knocking him unconscious. Nate then proceeds to an injured Elena by the helicopter where she then warns Nate that Navarro has regained consciousness and is prepared to kill them both with his shotgun. Nate pushes the helicopter off the tanker where the falling helicopter takes Navarro and the statue down into the ocean.
Elena gives Nate the ring back that he left with Sir Francis and they both lean in for a kiss, but is interrupted by Sully that arrives with a speed boat filled with boxes of treasure he stole from the pirates. As they sail off into the horizon Elena reminds Nate that her camera is still broke and he still owes her a story, Nate tells her “I’m good for it”.
