Santaro Ishihara, a just-fired supermarket salesman, accepts a job teaching at the inhouse school at the Sakuragaoka General Hospital. "MR. RED NOSE" follows Ishihara's journey as he tries to convey his faith and optimism to his students while also learning from them about their own methods of coping with their illnesses.
Ishihara's students suffer from serious illnesses like leukemia, kidney disorders, asthma and diabetes. On his first day at school, Ishihara wears a 'red nose' and attempts to amuse them but it only makes one of the students' condition worse.
After noticing Wada is in love with a girl in another ward, Ishihara meddles in his affairs and makes the girl attend the in house class. Contrary to his expectation, Wada gets angry and runs out of the classroom.
Unlike Tagawa, the harder Ishihara tries to make the students laugh, the more he fails. To have at least one student like him, he makes an effort to get along with Tanaka, but she ignores him and throws her manga out of the window.
Ishihara decides to take his students to the sunflower field as an extracurricular activity to help them release stress. Meanwhile, Wada's health has deteriorated and when his father learns of this, he tells Ishihara to lie so that Wada will never know the truth. But then Wada's condition starts ...
A strange man enters the room during class, but he turns out to be Sakurayama's older brother and informs them of the hospital reformation along with the closure of the inhouse school. Upon Ishihara's objection, he fires Ishihara.
While Yaegashi will soon be discharged from the hospital, Ishihara continues to give lessons to Wada who remains unconscious. Ishihara sees a diploma has been made for Yaegashi and wonders if something can be done for all the students just before the closure.