[1][2] Setchell showed an early interest in natural history that was furthered during his years at the Norwich Free Academy.

[3] After completing his PhD in 1890, Setchell took a post at the Sheffield Scientific School of Yale University as an assistant in biology.

[3] He initiated a series of UC publications on botany and built up the University Herbarium and botanical gardens.

[3] In the early 1890s, Setchell teamed up with botanists Frank Shipley Collins and Isaac Holden to create specimen collections of dried North American freshwater and marine algae.

[3][7][8] Each collection was mounted on pages bound together in a book form, with printed labels and an index, and issued in an edition of 80.

[3] Possibly his most important contribution to American botany was the multi-volume reference work Algae of Northwestern America, on which he collaborated with fellow UC Berkeley botanist Nathaniel Lyon Gardner.