The game's story takes place about four years after the beginning of Atelier Ayesha: The Alchemist of Dusk in a far away place to the west of the Twilight Land where the local administration hires two new alchemists, Escha and Logy as members of their R&D division. While learning the ropes of their new occupation, Escha and Logy gather friends and companions as they unlock the secrets of the nearby ruins and help the citizens in a world that is still recovering from a catastrophic event known as "The Dusk".
Atelier Escha & Logy will allow players to choose between two protagonists. The main storyline will remain the same regardless of who is chosen, but certain events and ending will only be available on a particular protagonist.
With the new synthesis system, the player can combine different items. The two protagonists Escha and Logy use different kinds of tools to synthesize.