The son of a carpenter, he grew up in dire poverty and as a child witnessed the sale of his older sister into the life of a geisha, an event that was to have a profound influence on his work in films. At age 13 he quit school to work in a hospital and at 17, after his mother's death, he left home to live with his geisha sister. Drawn to the graphic arts since childhood, he now enrolled at an art school specializing in Western-style painting. At 19 he went to work for a newspaper at an advertising designer. In his spare time he wrote poetry and organized a stage group that performed in the open air. At 20 he entered Japanese cinema as an actor and was soon moved to the position of assistant director. He made his debut as director in 1922.

In a career that spanned 34 years, Mizoguchi made more than 80 films, many of which rank among the finest in Japanese cinema. Two of these, The Life of Oharu (1952) and Ugetsu Monogatari / Ugetsu (1953), are acknowledged masterpieces of world cinema. Mizoguchi approached his films with the eye of a painter and the soul of a poet. Shunning frequent camera setups and disruptive close-ups, he developed a visual style rich in beauty and physical and psychological detail. He emphasized the internal design of his images, creating aesthetically pleasing compositions, then explored them lovingly and at length with gentle camera movements. He thus created a realistic and unified universe, concrete in mood and atmosphere, in which he proceeded to explore the psychological interplay of his characters. His main theme was the social condition of the Japanese woman and her role in a society polarized between traditional and modernizing forces. His interest in and profound understanding of female psychology are consistent features of his films.

A fragile man afflicted with crippling rheumatism from childhood, Mizoguchi died of leukemia at 58.