The plot of Part I is exactly the same as the original, with a new virus turning humans into hostile infected and being set 20 years after such. It follows a hardened survivor Joel and an immune teenager Ellie crossing across a post-apocalyptic United States in order to find a group called the Fireflies, who would be able to create a cure against the disease by studying Ellie's immunity.

Similar to the original game on PlayStation 3 (and remastered for the PS4), The Last of Us Part I is an action-adventure game with survival horror elements, played from the third-person perspective. The game was rebuilt from the ground up using Naughty Dog's latest engine on the PS5, leveraging the leap in technology with its powerful hardware. The game implements modernized gameplay, improved controls and performance, and expanded accessibility options closer to that of 2020's The Last of Us Part II. Visual fidelity, effects, exploration, and combat have all been enhanced as well. The game also supports PS5 hardware features including 3D audio and the haptic feedback and adaptive triggers of the DualSense controller.

In April 2021, Jason Schreier of Bloomberg first reported that a remake of The Last of Us was being secretly developed by Naughty Dog for the PlayStation 5. He noted that the project was originally being developed by the Sony's Visual Arts Service Group studio, however, Sony grew dissatisfied with the studio's progress on the game. Sony reconfigured them into a support studio and tasked Naughty Dog with developing the project, partially due to their other planned titles being at various stages in pre-production and a lack of familiarity with the PS5's hardware. The remake was helmed by game director Matthew Gallant and creative director Shaun Escayg.

The Last of Us Part I was officially announced by Sony at the Summer Games Fest on June 9, 2022. Just prior, a listing of the game was accidentally leaked on the PlayStation Direct website, revealing the game prematurely. A trailer was released with the announcement and a release date was set for September 2, 2022, for PlayStation 5 and a later date for Microsoft Windows. They also announced three retail editions of the game available for pre-order: Standard, Digital Deluxe, and Firefly.

The Last of Us Part I is available in three editions. The Standard Edition ($69.99 USD MSRP/ $89.99 CAD MSRP/ €79.99 EUR MSRP) includes just the base game as well as the standalone prequel chapter Left Behind. The Digital Deluxe Edition ($79.99 USD MSRP/ $99.99 CAD MSRP/ €89.99 EUR MSRP) allows the player to unlock several items and skill upgrades early, as well as a gameplay modifier, render mode, and six weapon skins. The Firefly Edition ($99.99 USD MSRP) includes all the aforementioned features plus a SteelBook display case and all four issues of The Last of Us: American Dreams, each with their own new cover variant. This edition is only available for order in the United States via the PlayStation Direct website.