Serpieri studied painting and architecture at the Fine Art Academy in Rome as a child. He studied under Renato Guttuso, one of the major Italian painters of the 20th century. Serpieri began his painting career in 1966 achieving much acclaim from the critics, but shifted to the comic book industry in 1975 when he took on work from the Italian comic magazine Lanciostory.
Serpieri published Morbus Gravis in 1985, which featured the first appearance of Druuna and launched the Druuna saga. The series is known for its explicit content including graphic violence, sex, and realistic artwork. The saga is extremely successful, selling more than one million copies in twelve different languages. Heavy Metal publishes the English language versions. Serpieri has published many sketchbooks due to the interest in the Druuna series. His high detail in his art and the portrayal of his well-endowed heroines has earned him the title of "Master of the Ass".