Nathan Drake is a rough-around-the-edges, modern-day treasure hunter who sets off to continue his great ancestor's, Sir Francis Drake, quest for the lost city of El Dorado. With the help of long time friend and mentor, Victor Sullivan, and the tag-along reporter, Elena Fisher, Drake raises Francis Drake's coffin from the bottom of the ocean to find that Drake faked his death, and left his diary as a clue for anyone clever enough to find it to use.
Ditching Elena at the next port, Drake and Sulley follow the diary to an empty tomb, once housing a golden idol... a huge golden idol. Drake realises that El Dorado wasn't a city, but this missing idol, and prompts him and Sulley to continue the search. After stumbling upon an old German U-Boat in the middle of the Amazon, Drake gives Sulley the diary and explores inside to find a map and coordinates in the Captain's Quarters, pinpointing the location of the moved treasure.
When Drake returns, he finds Sulley and himself held at gunpoint by Gabriel Roman and Atoq Navarro after revealing that Sulley is in debt to Roman and the treasure would greatly make up for it. During negotiations, Roman shoots Sulley dead... and as the U-Boat explodes Nathan makes his escape at which point he reunites with Elena.
Drake and Elena escape and continue the search for El Dorado. While flying to a mysterious, forgotten island in the middle of the Pacific, Drake's plane is shot down and Elena and Nathan parachute out, ending up separated.
Nathan hurries to find Elena but is captured when he attempts to save her. Elena returns the favour by breaking him out of his jail cell and driving the getaway Jeep while Nathan fights off the pursuers. Trapped and out of road, Nathan and Elena stall for time as Eddy Raja, a long time rival of Nate's, attempts to take back the map. Drake makes a daring escape which buys them a little more time.
As Drake and Elena explore more of the island, they find out Sulley's still alive. Once reunited, Sulley reveals Drake's diary took the bullet for him and they use the diary to unlock more secrets of the island. As they get closer to the treasure, more of the island's darker secrets are revealed and Nathan pieces together that Francis never wanted the treasure, but wanted to get rid of it... for good.
After taunting Drake, Roman and Navarro capture Elena and thank him for leading them to the treasure. Now.. it's personal. Drake realises he can't let El Dorado leave the island and as Navarro air lifts it out of the temple, Nate jumps from a cliff and hangs onto the cargo net. As one of Navarro's men leans out of the helicopter to shoot Drake, Elena kicks him out of the copter, causing him to shoot the pilot as he falls to his death.
Navarro crash lands the copter on his escape ship as Drake drops from the net onto the deck and takes cover for the final showdown between him and Navarro. Drake and Navarro fight hand to hand, and while Navarro's down, Nathan rescues Elena from the helicopter teetering on the edge of the landing pad. Elena warns Nate that Navarro's on his feet and Nate ends this battle with style. As Navarro stands, Drake pushes the copter off the ship, tightening the rope around Navarro's leg and dragging him to the bottom of the ocean along with the cursed idol of El Dorado.
As things calm down, Nathan and Elena stare into the sunset and lean in to kiss... just as Sulley interrupts with the rescue ship, full of gold he stole off some pirates who were "too dead to care." As Elena reminds Drake he still owes her a story, he assures her he's "good for it" and wraps his arm around her while they sail off into the sunset.