Co-director Neil Druckmann snuck in several Easter eggs which directly referenced The Secret of Monkey Island, including the likeness of its main protagonist Guybrush Threepwood. Naughty Dog later received permission from The Walt Disney Company to leave these references in the game.

In Chapter 11, a slightly burned portrait resembling Guybrush can be found that Nathan and Sam will comment on, not recognizing him among the other pirate founders of Libertalia they do know. This is hinted at further during the sigils puzzle in the same chapter, one of which is that of a monkey. A statue of the Guybrush figure can be found among statues of the founders during Chapter 12, with Nathan again conveniently forgetting his name. Spoiler:A more intact version of the painting can be found later in Chapter 15, but with the word "THIEF" painted overtop its subject as are the rest of the portraits found near it, and a barely legible plaque underneath revealing his name to be "Guy Wood". In Chapter 18 while in Thomas Tew's mansion, Nathan and Elena stumble upon a dinner table surrounded by the corpses of the founders. Guy Wood's corpse appears among the rest, with a monkey sigil found close to him on the table.

Two more references to The Secret of Monkey Island can be found in the game's dialogue, including one moment where Nathan comments "That is the second biggest cistern I've ever seen." This references a running gag from the series where Guybrush would commonly remark that something is the second biggest version of that thing that he's seen. The second piece of dialogue refers to Monkey Island itself with the line "Big, skull-shaped island? What?"

According to an interview with Neil Druckmann, Cassie Drake was originally going to be a male character, but this was change their female lead character concept artist. The artist wanted Nate & Elena's child to be a girl, and Neil was convinced by her decision.

In an interview with Neil Druckmann, it was revealed that the "Doughnut Drake" skin would not return in Uncharted 4, due to being offensive to people who are overweight.

Standing still after a cutscene in chapter 11 will give you the achievement "Stage Fright". This is in reference to Sony's press conference at E3 2015, when a glitch rendered Nathan unable to move in Sony's demonstration of the game.

In Uncharted 4, there is an Easter egg to one of Naughty Dog's earlier franchises, Crash Bandicoot. Spoiler:Nathan Drake has to play the first Crash Bandicoot game and beat Elena's high score, and only has three chances to do it. If Nathan fails three times, he will be mocked by Elena.

Drake's costume went through a number of different designs, all specifically designed to not stand out. The designer wanted to have all of Drake's accessories and his outfit to not distract from the motion actor's work and Drake's facial features but also to portray that he had not been going on adventures for some time.