Mark H. Hollender graduated from the University of Illinois College of Medicine in 1941 and went on to Cook County Hospital in Chicago as an intern. After serving in the U.S. Army Air Force Medical Corps at convalescent hospitals in Nashville and Plattsburgh, New York, Hollender decided to enter the field of psychiatry. Upon completing his military service, he became a resident in psychiatry at the Illinois Neuropsychiatric Institute at the University of Illinois. In 1951 Hollender graduated from the Institute of Psychoanalysis in Chicago.

After some time in private practice, Hollender was appointed Professor and Chair of the Department of Psychiatry at the State University of New York, Upstate Medical Center, where he served from 1956 to 1969. Hollender was then recruited to be chair of the Psychiatry Department at Vanderbilt University Medical Center, where he worked from 1969 to 1989.