He was born into a family of artists, and learned to paint from his father Herman, along with his brothers Abraham and Herman Saftleven the Younger. He lived for a time in Utrecht with his brother.
After training in Rotterdam, possibly with his father, Cornelis traveled to Antwerp around 1632. Among his earliest works are portraits and peasant interiors influenced by Adriaen Brouwer. By 1634 Cornelis was in Utrecht, where his brother Herman Saftleven the Younger was living, and the two began painting stable interiors, a new subject in peasant genre painting. By 1637 Cornelis had settled in Rotterdam, where he became dean of the guild of Saint Luke in 1667. His subject matter was varied, from rural genre scenes to portraits, beach scenes, and biblical and mythological themes. His images of Hell may be his most individual contribution to Dutch painting. Equally innovative were his satires and allegories. Saftleven excelled at painting animals and often portrayed animals as active characters, occasionally with a hidden allegorical role. As a draftsman, Saftleven is best known for his black chalk drawings of single figures, usually young men, and his studies of animals, which show Roelandt Savery's influence. About two hundred of his oil paintings and five hundred drawings survive. 
Saftleven's subject matter covered various subjects, including genre works, portraits, beach scenes, and biblical and mythological themes. Some consider his images of Hell to be his most individual contribution to Dutch painting 
Approximately two hundred of his oil paintings and five hundred of his drawings still survive.