The Walking Dead: Survival Instinct is a first-person shooter game based on The Walking Dead television franchise, rather than the original comic book franchise. It also acts as a prequel to the TV series. The protagonist is Daryl Dixon and the story focuses on Daryl and his brother Merle as they travel to Atlanta through the Georgia countryside in the early days of the zombie apocalypse. Initially it is only Daryl and Jess Collins who escape from a mountain shelter to gather supplies after the death of Daryl's father, but later they are joined by Warren Bedford and finally Merle.

The game is played as a first-person shooter, but when zombies get too close and grapple Daryl, he is able to perform a brutal melee attack with various weapons as a quick time event. Many confrontations can be avoided by sneaking around. Next to the regular weapons such as shotguns, pistols and rifles, a crossbow can be found later on for silent kills. Stealth melee kills can also be performed by sneaking up on walkers. They can be distracted by throwing glass bottles in a certain direction. Each level has a main objective with a number of optional ones and they are largely linear in design.

Travelling between locations is done with a vehicle and the route can be determined by the player. In the menu the player can choose to drive fast without stopping, or slower with the option to plunder. Back roads are slower but offer more opportunities to plunder, while highways are faster but can cause the vehicle to break down and then new car parts have to be found in mini-missions. Very often new fuel for the vehicle needs to be found to continue driving. While on a looting mission, the other characters can be tasked to look for supplies (but risk injury) or to wait by the car. Room in the vehicle is only limited, so at various points a certain character can be dismissed when someone else offers to join the group. Characters are managed in menu screens. The player can review traits, health, equip a weapon, provide a task and determine the risk.