Aegis of Earth: Protonovus Assault is set 50 years after the so-called "Silent Apocalypse", a catastrophe that brought monsters into the world with only one goal - killing all remaining humans. These creatures have gathered in a few remaining cities powered by the new element altenite.
The game is a tower defense game, where monsters attack the city in waves and are shot down by defence machines bought by the player. There are different enemy types that are vulnerable to certain weapons, and the speciality of this game lies in constructing the cities as rings, which can be rotated individually during battle to meet the requirements of the current attack.
Between attacks, there is an unlimited planning phase where the player develops their city: buying more weapons, upgrading them, or taking care of other things like structures for refugees and research of advanced weaponry. Later in the game, the player takes control over multiple cities, including the option to jump back and forth via a world map.
The frame story is mostly told in dialogues between an anime cast of characters. The involved people are also present during battles and may trigger their special ability, but the player has no direct influence on this. The character's focus level determines which ability is activated, with options to keep them focused high by personal interactions like thanking a team member after a mission.