During his lifetime, Herman Saftleven was one of Holland's best-known artists. His father and his elder brother Cornelis probably trained him. His simple, austere style appears in an early series of landscape etchings from 1627. Around 1632, Saftleven made Utrecht his home. In the following year, he collaborated with Cornelis on paintings of rustic barn interiors, a subject that later became something of a specialty for him. In 1635 he helped to decorate Prince Frederick Henry's palace of Honselaersdijck, south of The Hague. His Italianate landscapes reflected Cornelis van Poelenburgh's style, but by 1645 Saftleven had abandoned that manner for native Dutch scenery. Over 1,200 of Saftleven's landscape drawings survive, mostly large-scale compositions for collectors. He also made precise drawings of sites from his travels around Utrecht and along the Rhine. By the 1650s, influenced by Roelandt Savery's art, Saftleven was drawing imaginary panoramas of topographically accurate hilly and rocky landscapes recalling the Rhineland. He was also an active etcher and engraver.
Saftleven repeatedly drew his adopted city of Utrecht. In 1675 he recorded its houses and streets after hurricane devastation. In his last years, he made botanical studies in watercolor.