Ranged weapons usually have a limited amount of ammo and require ammo pick-ups to keep using them. Levels contain random chests with weapons such as a revolver, machinegun, smart gun, minigun, shotgun, rifles, an incinerator, sluggers, bows, grenade launchers and bazookas, but also melee weapons such as a wrench or a screwdriver. When all enemies are defeated a vortex appears that sucks the character into the next level. Levels are short and always consist of a single, scrolling room. The game is played as a twin-stick shooter where both movement and firing in any direction can be independently combined. Next to the basic attack each character has a unique secondary action such as a roll or forming a shield, along with a general perk. There is permadeath and up to twelve different playable characters can be unlocked, representing different playing styles. Many levels contain bosses with a brief introduction. It consists of several levels played in succession, each with a different theme, until the character gets a shot to claim the nuclear throne and become the new king.

Typical for the genre the game is meant to be played in multiple runs, with randomized environments, and weapon and monster placement for each session. The developers then started work on a full version and took it to Steam's Early Access. The game was initially started as Wasteland Kings, a prototype created for the 2013 Mojam game jam. Nuclear Throne is an action roguelike game set in a post-apocalyptic wasteland filled with mutants.

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