The game is set in the United States at the start of a zombie outbreak. It takes place in the original universe but does not rely on characters or locations from the comic book or the TV series. Instead it tells a parallel story through a new character Lee Everett, but some original comic characters such as Glenn and Hershel make a cameo appearance throughout the series. The main protagonist Everett was a professor at the University of Georgia who was convicted for murder when he came home one day and found his wife cheating. In a fit of rage he murdered the man and was convicted. At the start of the game Everett is transported to prison, but the car crashes and that way he manages to escape. His main concern is then to flee from the zombies and he plans to travel to Macon where his parents and brother live. He soon meets a small girl called Clementine whose house has been overrun by zombies and he takes her along. Afterwards he meets many more characters and travels to different locations. Much of the game is spent on the emotional bond with Clementine and how Everett chooses to carry her through the hostile environment.

It is played as an adventure game with action and role-playing elements. During many sequences the character can freely look around the environment and interact with items. Compared to Telltale's previous title Jurassic Park: The Game there is slightly more freedom in exploration and more traditional adventure game elements such as examining objects, storing them in an inventory, and applying them in the environment. Many of the action sequences are shown as a cinematic or through quick-time events for the player to act quickly. When they are not performed in time, the character dies, and often Everett also has the option to save characters or to let them die in the hands of the zombies. There is a rewind function that provides the option to return to any of the eight chapters in an episode to choose a different option without having to replay the entire episode. There are sequences with a stealth mechanic where Lee can pick for a short amount of time and then needs to get back before he is discovered and gets killed. While exploring different icons show actions such as examining, interacting or using an item. Inventory items also appear here and the player does need to interact with the inventory or combine items before they can be used.

During conversations there are multiple options that can alter the outcome of events. A timer runs down during a conversation option and if none is chosen there is one selected by default. At the start of the game two display styles can be chosen. Standard shows more of the UI and helps with important choices, while Minimal turns of UI hints, help, and choice notifications. The setting can still be altered mid-game. Crucial choices during events and conversations are remembered and carried over to next scenes and episodes. Each episode ends with a cliffhanger, a sneak preview of the next episode, credits, and an overview of the crucial choices and how they compare, shown as percentages, against the choices of all other players worldwide. A new episode starts with a flashback of the previous events, dynamically incorporating the player's choices. It is a much darker title than Telltale's previous games and as it includes cursing and gruesome killings, but the focus is on the moral choices and consequences in a violent environment.