Based on the Spyglass Pictures feature film, Reign of Fire for the Game Boy Advance is set in a post-apocalyptic near future, in which dragons rule the Earth and human beings struggle against extinction. The game is split into two parts, allowing players to take the role of the technologically savvy humans or the evolutionarily accelerated dragons.

Each side has its own full campaign of 20 missions. As the human campaign progresses, players gain access to a variety of vehicles and weapons to turn the tide in their favor. As players fly through the dragon campaign their beasts continually evolve, gaining new powers to help assert their dominance once and for all.