Originally hired as a professor in the Life Sciences Department, he was responsible for administering UCR's change from a liberal arts college to a major research university.
Graduating in 1926, he went on to Indiana University Bloomington, where he worked under Alfred Kinsey studying the evolution and taxonomy of mayflies, and received his Ph.D. in 1931.
During the Second World War, Spieth was a captain in the United States Army Air Forces, serving as head of the Navigation Department at Cochran Field in Macon, Georgia, and later as assistant director of the School for Altitude Physiology in Florida.
He became friends with Theodosius Dobzhansky at Columbia University and Ernst Mayr at the American Museum of Natural History, both of whom encouraged him to explore the mating behavior of Drosophila.
A new period of Spieth's professional life began with his move, in 1953, to a newly established Riverside campus of the University of California.
His term as chancellor was busy as he presided over the change to a general campus, directed the construction of new buildings, established the Philip L. Boyd Deep Canyon Desert Research Center, facilitated the development of graduate programs and successfully managed the "student problems of the 60s" which entailed the delicate task of maintaining order while protecting academic freedom.
He also acquired undeveloped land on the campus for field research which subsequently was designated the Herman T. Spieth Natural History Preserve.
He first worked out the basic experimental techniques for analysis and then proceeded to describe the evolution of mating behavior throughout the genus, which was a pioneering contribution to a now flourishing field.
His final years were spent studying the ecology of Drosophila in the Blodgett Forest in the Sierra Mountain Range near Davis.