The game is considered to be a spiritual successor to the Left 4 Dead series, and carries over several key gameplay pillars,[2] such as a strong emphasis on cooperative teamwork, and an AI system called the "Game Director", which dynamically modifies the environment, placement of enemies, items, and obstacles in response to players' progression and behavior.

[4] The game features pre-defined hero characters who have preset attributes and abilities, and players can purchase upgrades and items with an in-game currency called Copper.

A group of veteran survivors called the "Cleaners" fight the Ridden and defend Fort Hope, a settlement within fictional Finleyville, Pennsylvania.

[5] In the primary game modes, the player can control one of 12 Cleaners: Walker, a United States Army Ranger veteran and de facto leader of the Cleaners; Chris, the eldest Cleaner nicknamed "Mom" because of her maternal attitude; Holly, a brash fighter who wields a baseball bat named Dotty; Evangelo, an optimistic recruit; Hoffman, a socially awkward survivalist and conspiracy theorist; Seo-yeon, who is nicknamed "Doc" for being the group's medic and scientific expert; Jim, an experienced hunter and marksman, Karlee, a cynical lone wolf, Heng, a survivalist and chef at heart, Sharice, a tough as nails former firefighter, "Prophet" Dan, a protector for "the light's chosen", and the newest cleaner, Tala, a former cult member of the children of the worm.

The game's campaign begins with Walker, "Mom", Evangelo, and Holly, arriving at a settlement in Evansburgh to trade supplies.

As the team retreats to Fort Hope, their commander, General Phillips, has them demolish the Washington Crossing Bridge to delay the Riddens' advance.

Phillips sends the Cleaners to another location to extract Doctor Rogers, a scientist who has developed a chemical weapon called T-5 that is significantly effective against the Ridden.

During this time, the Cleaners Heng and Sharice join the team due to the surge of "Ridden Hives" which are popping up across Evansburgh and Finleyville.

Phil Robb, the game's creative director, added that the Cleaners are more confident and capable, unlike the everymen from Left 4 Dead.

In January 2022, during a Reddit AMA, Turtle Rock Studios confirmed plans for future paid downloadable content, to which new characters will be tied to.

This expansion introduces a playable cleaner named "Prophet" Dan, an act for the player-versus-environment campaign mode and four new enemies.

In January 2023, Turtle Rock announced that they had shifted their development resources to their next project, and no additional content updates would be released for Back 4 Blood.