The story is set some time before the events of Uncharted: Drake's Fortune, and begins in medias res with Nathan Drake following rival explorer Jason Dante through a temple complex in Panama. Dante has ordered his army of mercenaries to kill Drake on sight, and after a series of gunfights, Drake is apparently killed in an RPG explosion.
The game then flashes back two weeks, when Drake and Dante, revealed to be old friends, arrive at a dig site in Panama headed by Dante's "partner" Marisa Chase, who doesn't trust him. At the site, they find corpses of Spanish conquistadors that were apparently poisoned and a grave marker with a Visigoth symbol. Chase also shows Drake an amulet that she hid from Dante. The dig is then interrupted by Dante's real partner, warlord Roberto Guerro. Guerro captures Drake and Chase, however they escape Guerro's base after Chase starts a diversionary fire.