During development, several of the developers thought the game would ruin Naughty Dog's reputation and tank completely, leading to the studio's downfall. The game eventually wound up winning multiple game of the year awards and was praised by critics and gamers alike.

When you unlock all the "Shiv Doors", you'll get a trophy called "Master of Unlocking". This is a reference to Barry Burton's infamous quote to Jill Valentine, when he gave her a lockpick in Resident Evil (1996).

In the prologue, if the models of Joel and Tommy were removed, the game will crash after Sarah gets into the car with them, and restarting the checkpoint will allow the player to roam around some areas, from the glitched car to the Louis' burning farm.

In The Last of Us Remastered's commentary with director Neil Druckmann, he stated that him and the team initially didn't want to do an opening credits sequence. They changed their minds, partially because they felt that going from Sarah's death to a timeskip of twenty years later was too sudden. On top of that, the team found that when playtesters watched it in succession, they weren't paying attention when Tess and the rest of the game's world was introduced, because they were still focused on Sarah's death, so an opening sequence was needed to help bridge the gap between those events. The idea they came up with for the intro was time lapsed video footage of fungus growing, because the disease and outbreak in the game was based on a cordyceps fungus that spread through spores. The team contacted a group at Sony San Diego who made the whole opening sequence for them, making use of fungal kits to allow fungi to grow in their bathrooms, which took several days of filming to produce. The only use of computer animation in the opening sequence were the black spores seen throughout the intro.

In The Last of Us Remastered's commentary with director Neil Druckmann, he stated that there was originally going to be dark music during the scene when Marlene revealed that Ellie was going to be sacrifice for a cure. However, Druckmann told the composers not to do that, because it would paint her as a bad person rather than a good person who is trying to save humanity. Instead, he let them use the dark music for Joel, because when Ellie's life is on the line, he slips back into murdering anyone who would try to kill her. Neil also stated that this scene defined the theme of the game: "as a father... you will... kill everybody else to save your kid."

In The Last of Us Remastered's commentary with director Neil Druckmann, he stated that Jeffrey Pierce originally auditioned for the role of Joel, which ultimately ended up being given to Troy Baker instead. When the team began finding someone to cast as Tommy, they called Pierce back in and were impressed with his performance, landing him the role of Tommy. Baker stated that he felt a chemistry between himself and Pierce that made for a sense of realism in Joel and Tommy's relationship.

Druckmann also stated that Ashley Scott was originally intended to play Tess instead of Maria, and that there were no auditions for either of those characters.

In The Last of Us Remastered's commentary with actress Ashley Johnson and director Neil Druckmann, in the scene where Joel found Ellie in the abandoned house, Ashley stated that she improvised by shoving him out of frustration, because she felt emotional reading for the scene where Joel is planning to leave her to Tommy.

Druckmann stated that the team wanted him to remove this scene where Joel is being too cold to Ellie, but he refused because he felt it was important to keep in the scene that Ellie is "being so vulnerable and [Joel is] having these feelings. He's trying to shut it down". Druckmann also commented that when Joel said to Ellie "You're not my daughter", he stated that while that quote is almost an insult, it's the opposite of what he actually feels.