Throughout the game, the player is given reason to be suspicious as strange happenings are going on around them, and a severely irradiated Pokémon looms over the region, ready to destroy it all. The player's mother has been lost after an explosion at a nuclear power plant, and their father, Kellyn, remains cold and distant as he throws himself into his work to avoid dealing with his grief, leaving the child with their aunt. The protagonist receives a Pokémon they choose from the new Pokémon Professor Bamb'o, and set off. The story follows a young hero as they journey through the region, collecting a total of eight Pokémon gym badges and eventually defeating the Pokémon League to become the Pokémon champion. In Pokémon Uranium, the player navigates through the Tandor region, and encounter 200 Pokémon species throughout their travels, most of which are fan-made. Following the announcement, community members created a new website and continued to develop patches for the base game, including bug fixes and new features. The following month, the developers announced that they had officially ceased development of the title and shut down the website and servers.

In August 2016, after one and a half million downloads, the download links for Pokémon Uranium were taken down from the official website because the developers wanted to 'respect Nintendo's wishes', after receiving multiple DMCA takedown notice letters from lawyers representing Nintendo. Similar to the official games, Uranium contains both online trading and online battling.

The game adds 166 new fan-made species of Pokémon, with only 160 currently available, along with a new region. The game was in development for nine years, and used the RPG Maker XP engine. Pokémon Uranium is a fan-made game based on the Pokémon series.

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