"Valkyrie Drive -Mermaid-" is set in a world where a mysterious virus, the A Virus, infects young women, granting them the ability to transform into weapons known as "Arms." These women, called "Extars," must form partnerships with other Extars, known as "Liberators," who wield them in combat. The series primarily takes place on two isolated islands: Mermaid, a prison-like facility for Extars, and Bhikkhuni, a training ground for Liberators.

The protagonist, Mamori Tokonome, is a shy and reserved girl who becomes infected with the A Virus. After being transported to Mermaid Island, she encounters a confident and assertive Extar named Mirei Shikishima. When Mamori is attacked by hostile Extars, she transforms into a weapon, and Mirei wields her to fend off the attackers. This event marks the beginning of their partnership. As the story progresses, Mamori and Mirei navigate the challenges of Mermaid Island, uncovering its dark secrets and the true purpose of the A Virus.

The series explores themes of trust, partnership, and survival, as the characters form bonds to strengthen their abilities in combat. Mamori and Mirei are joined by other Extar-Liberator pairs, each with distinct personalities and motivations. The narrative delves into the origins of the A Virus and the organizations manipulating the Extars for their own agendas. The characters face moral dilemmas and confront the ethical implications of their powers and the experiments conducted on them.

"Valkyrie Drive -Mermaid-" combines action, drama, and elements of science fiction, with a focus on the relationships between the characters. The series balances intense combat sequences with moments of character development, highlighting the emotional struggles and growth of the protagonists as they fight to uncover the truth and protect each other.