According to an Electronic Gaming Magazine interview (published in Issue #224, January 2008) with Naughty Dog co-president Evan Wells and the game's director Amy Hennig, they were asked if they ever had plans for a different final boss battle after the interviewer expressed disappointment with it. Wells stated that the boss battle was designed to fit within the confines of the island and world they created, and that they could have made it more elaborate if they had a few extra weeks, but the overall direction remained consistent with their original plan. Hennig added that many games face the issue of jumping-the-shark at the end, as they need to escalate to a climax. She contrasted this with movies, which "get away with less" as they focus more on narrative and emotional experiences, and suggested that game design might benefit from shifting away from traditional boss battles to creating peaks in the overall experience.

The German language version of the game removed all references to the word "Nazis" from the game's dialogue:

• In "Chapter 3 - A Surprising Find", the word "Nazis" is replaced with "crew" when Nate and Sully came across a U-857 (German U-boat).
• At the end of "Chapter 17 - The Heart of the Vault", references to Nazis are simply replaced with the word "they".

Sir Francis Drake's motto "Greatness from small beginnings." was a mistranslation, the actual motto of Francis Drake is "Thus, from small beginnings, Great Things Come."

At the end of Uncharted, Spoiler: Nate and Elena are about to kiss but are interrupted by Sully. This might be a reference to Jak and Daxter, in which Spoiler:Jak and Keira get interrupted by Daxter before they kiss in every game. Both series were developed by Naughty Dog.

Victor Sullivan's private seaplane, Hog Wild, is a reference to a level found in Crash Bandicoot.