Kousei Arima is a child prodigy known as the Human Metronome for playing the piano with precision and perfection. Guided by a strict mother and rigorous training, Kousei dominates every competition he enters, earning the admiration of his musical peers and praise from audiences. When his mother suddenly passes away, the subsequent trauma makes him unable to hear the sound of a piano, and he never takes the stage thereafter. Nowadays, Kousei lives a quiet and unassuming life as a junior high school student alongside his friends Tsubaki Sawabe and Ryouta Watari. While struggling to get over his mother's death, he continues to cling to music. His monochrome life turns upside down the day he encounters the eccentric violinist Kaori Miyazono, who thrusts him back into the spotlight as her accompanist. Through a little lie, these two young musicians grow closer together as Kaori tries to fill Kousei's world with color.

The United States of America has been in chaos ever since the emergence of D2s, an invasive species originating from a black meteorite that fell to Earth. A public decree banned citizens from playing any melodies, to prevent further casualties caused by the D2s' hatred for music—even now, in 2047, this prohibition is still in effect. Humanity's only form of defense against the D2s are Musicarts, young women representing pieces of classical music; and Conductors, the ones controlling them. Takt Asahina, an aloof piano prodigy, finds himself transformed into a Conductor following a spontaneous D2 attack. The same incident kills Anna Schneider's younger sister, Cosette, and brings Takt into contact with his Musicart, Destiny. Searching for a means of stabilizing the pact between themselves, Takt and Destiny—alongside Anna—embark on a perilous journey to the Symphonica Headquarters in New York City. Takt is in a hurry to reach the city so that he can play the piano again, even though his passion attracts the creatures he has come to despise. Meanwhile, Destiny's sense of duty drags the group into trouble along the way. With a D2-infested path and many more arduous obstacles ahead of them, will the trio make it to New York City in one piece?

Now that Kumiko Oumae has enrolled in Kitauji High School, she hopes to forget about her past. Despite her desire for a fresh start, she gets dragged into the school's band club by her new friends—Sapphire Kawashima and Hazuki Katou—and is once again stuck playing the euphonium. As the band currently stands, they won't be able to participate in the local festival, Sunfest, let alone compete at a national level. The band's new advisor, Noboru Taki, gives them a choice: they can relax and have fun, or practice hard and attempt to get into nationals. Not wanting to repeat her mistakes from middle school, Kumiko is doubtful as to whether they should try for nationals. Amidst the chaos, she learns that her old bandmate, Reina Kousaka (who she had a bitter relationship with) has joined Kitauji's band club. Under the pressure of Noboru's strict training, Kumiko and her bandmates must learn to overcome their struggles and find success together.

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 Shinichi from leaving for Europe is his fear of flying. As a result, he's grounded in Japan. During his fourth year at Japan's top music university, Shinichi happens to meet Megumi Noda or, as she refers to herself, Nodame. On the surface, she seems to be an unkempt girl with no direction in life. However, when Shinichi hears Nodame play the piano for the first time, he is in awe of the kind of music she creates. Nevertheless, Shinichi is dismayed to discover that Nodame is his neighbor, and worse, she ends up falling head over heels in love with him.