The son of a factory owner and younger brother of Georg Escherich, Karl Leopold Escherich started out studying medical science in Munich and Würzburg and, after qualifying as a doctor of medicine, studied zoology in Heidelberg and Leipzig, where he received his doctorate. His academic career continued at Karlsruhe Institute of Technology, the University of Strasbourg, and the Academy of Forestry in Tharandt. He was appointed chair of applied zoology at the University of Munich in 1914.
He became involved in the Hitler movement early on, joined the Nazi Party in 1921, and took part in the Hitler putsch in 1923. However, he did not join the reorganized Nazi Party in February 1925 after it was banned. On October 15, 1933, he was appointed Rector of the University of Munich by the Bavarian Ministry of Culture, making him the first Rector no longer to have been elected by the faculties. And yet he was trusted by both sides. The state perceived him to be "a deeply nationalistic man and old admirer of Hitler" (Böhm, p. 532), while the university and its subdivisions regarded him as a figure of integration, a mediator, and a preserver of its own traditions.
Escherich was a full member of the Bavarian Academy of Sciences and Humanities from 1935 onward. He became professor emeritus in 1936, though served as visiting professor again from 1940 onward. Removed from office in 1946, he was reinstated in 1948 and simultaneously made an emeritus. The German Society for General and Applied Entomology has been awarding the Karl Escherich Medal, named for him, for outstanding scientific achievements since 1986.