Masane Amaha and her daughter Rihoko are on the run from a government child welfare agency that wants to take Rihoko away from her mother. They are caught and Rihoko is taken away. Meanwhile, Masane is attacked by an advanced weapon that can disguise itself as a human being. When faced with the danger, a strange light emits from her wrist and she transforms into a powerful being. She becomes involved in a power struggle between powerful organizations, with her at the center of their attention because she holds the greatest power of them all, the legendary Witchblade.

Shinichi Chiaki is a first class musician whose dream is to play among the elites in Europe. Coming from a distinguished family, he is an infamous perfectionist; not only is he highly critical of himself, but of others as well. The only thing stopping Chiaki from leaving for Europe is his fear of flying. As a result, he's grounded in Japan. During his 4th year at Japan's top music university, Chiaki happens to meet Noda Megumi—or as she refers to herself, Nodame. On the surface, she seems to be an unkempt girl with no direction in life. However, when Chiaki hears Nodame play the piano for the first time, he is in awe at the kind of music she plays. To Chiaki's dismay, Nodame moves into the apartment next to his and finds out that she is head-over-heels in love with him.

Tomoya Okazaki is a third year high school student resentful of his life. His mother passed away from a car accident when he was younger, causing his father to resort to alcohol and cigarettes. This results in fights between the two until Tomoya's shoulder is injured in a fight. Since then, Tomoya has had distant relationships with his father, causing him to become a delinquent over time. While on a walk to school, he meets a strange girl named Nagisa Furukawa who is a year older, but is repeating due to illness. Due to this, she is often alone as most of her friends have moved on. The two begin hanging out and slowly, as time goes by, Tomoya finds his life shifting in a new direction.