Between playthroughs, players can travel to an area called the Breach, where they can converse with non-player characters and unlock new items randomly encountered while playing.

Dodge Roll designed and playtested each individual room of the Gungeon's levels, and used procedural generation to assemble them into a random configuration.

Many of the guns were inspired by earlier games such as Mega Man and Metroid, while other mechanics were implemented to encourage players to utilize the layouts of levels.

[9] The layout and rewards of each level are procedurally generated from a number of pre-created rooms,[1] and are inhabited by bullet-shaped enemies called Gundead.

[10][11] To defeat Gundead, the player must use a wide variety of guns and items; they can be obtained by unlocking chests with keys or through shops and boss fights.

[1][11][12] As players slay enemies, they obtain in-game currencies (Contextualized in the form of bullet casings) and keys; the former can be spent at shops in exchange for guns and items, and the latter can be used to unlock chests.

[13][14] Obtained guns can range from conventional pistols and rifles, to more exotic firearms such as a unicorn horn that fires rainbows or a mailbox that shoots envelopes.

[1] Similar to other roguelikes, Enter the Gungeon has a permadeath system; If the player dies, they lose all items and guns obtained on a playthrough and must start again at the first floor.

[12][16] Both actions involve spending an in-game currency acquired from defeating bosses, with unlocked guns increasing the weapon options available on a playthrough.

[18] Similarly, they included usable environmental features such as flipping tables or bringing chandeliers down onto enemies to encourage the player to interact with and use the environment to their own advantage.

[25] A second major update, "Advanced Gungeons & Draguns", was released on July 19, 2018, for all platforms, which among additional weapons and enemies, was aimed to provide means to play the game that are friendlier to inexperienced players, but still offer more challenge for others.

Dodge Roll released a final free patch, "A Farewell to Arms", in April 2019 to fix lingering bugs and provide one last set of content updates.

[16][43][44][45] Destructoid drew comparisons between the dungeons of Zelda and the difficulty of Nuclear Throne, saying "While it doesn’t totally reinvent the twin-stick shooter, it has all but perfected it.

[50] While previously yearning for easier levels of difficulty, Electronic Gaming Monthly considered it helpful for teaching players how to improve their skills.

[2] Likewise, both Rock Paper Shotgun and Nintendo World Report considered their troubles with gameplay to be the result of a lack of skill, and accredited the game for not having its difficulty be based upon an imbalance of mechanics.