The core premise remains a classic globe-trotting treasure hunt centered on established protagonist Nathan Drake, his wife Elena Fisher, brother Sam, and mentor Sully, with heterosexual romance and family resolution in the epilogue featuring their daughter Cassie. New original character Nadine Ross, a capable South African woman who defeats Drake in a fistfight, and minor creative decisions such as changing the epilogue child from son to daughter and the mansion owner to a woman, reflect director Neil Druckmann's stated intent to incorporate more female characters after consulting Anita Sarkeesian-style critiques of representation.

These elements are noticeable but incidental to the adventure-driven plot and do not form the premise or primary emotional driver. No LGBTQ+ content, pronoun customization, queer romance, or source-material character swaps appear. Developer focus-testing backlash over the Nadine fight and daughter reveal, plus casting a white actress for the black character Nadine, generated limited contemporary discussion but did not alter the traditional storytelling framework or produce lasting reception gaps on Metacritic.