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A teenage girl named Mika meets a mysterious person on her way home, who warns her of horrifying events that are about to happen to her and her friends. More strange events are happening this evening: a cancelled meeting, a boy who seems to have followed her - but the next day, she almost forgets it... until she hears on the news that her schoolmate Kyoko was killed in a truck accident. Now Mika must find out what is truly happening around her. And so does Ryo, Kyoko's brother, who has been seeing strange dreams lately...

A spin-off of the Twilight Syndrome series, Moonlight Syndrome has a similarly text-heavy, low-interaction, linear gameplay with dialogue and/or action choices, which would sometimes influence the course of the narrative. Like Twilight Syndrome games (and unlike most Japanese-style adventure games), Moonlight Syndrome has physical character navigation in limited 3D areas. Some scenes - such as most full-screen dialogue portraits, etc. - are depicted as pre-rendered images. The player controls different characters, starting with Mika, then switching to Ryo; most of the gameplay consists of walking/running to the next screen, triggering the next dialogue/scene. There is no other interactivity in the game, and no items.