In 1939, Dorothy Hixon Clendening presented the Hixon Laboratory to the University of Kansas. One floor of the laboratory was established as a library devoted to medical history. At that time, Logan Clendening donated to the library his collection of works on the history of medicine, as well as in the basic sciences. Upon Dr. Clendening's death in 1945, his collection of approximately 6,000 volumes was bequeathed to the University of Kansas Endowment Association. It served as the nucleus of the rare book collection.

In 1957, a celebration was held for the opening of a new library building. At this time, the library consisted of current medical literature, along with reference books, textbooks, and the special "History of Medicine Collection." Faculty, student groups, medical departments, booksellers, other libraries, and friends of the library presented a "Dedication Gift" of twenty-eight rare books, prints, and photographs to the Collection. The new library also received a proper name: the Clendening Medical Library.

In 1983, the Archie Dykes Library for the Health Sciences opened. Current medical literature was moved to that location. On July 28, 1983, the Library received formal designation as "The Clendening History of Medicine Library." Earlier that year, the Executive Committee of the Medical Faculty met and unanimously approved a resolution recognizing that "the Clendening Library houses one of the most outstanding collections of books and artifacts relative to the history of medicine that exists in the United States". Further, they opined "that the continued growth and development of all aspects of human medicine will be best achieved if based upon the history of medicine".

Through the years, other faculty joined the History of Medicine Department or became interested in book collecting. Clendening's generosity was augmented by gifts from Ralph H. Major (history of medicine), Edward H. Skinner (radiology), Russell L. Haden (hematology), Thor Jager (Rudolf Virchow, pathology), Darrel T. Shaw (plastic surgery), Leonard F. Peltier (orthopedics), Walter Blount (orthopedics), and more. During the 1980's and 1990's, the Library continued to acquire rare books, both through gifts and through direct purchase. In 1998, the Library participated in the Haskell F. Norman Library of Science and Medicine sale at Christie's. Purchases included a collection of works on mesmerism and Georg Bartisch's Ophthalmoduleia. In 2014, hundreds of books were accepted back from Dykes Library into the Clendening collection as they reduced the physical holdings housed in their space.

Additionally during this time, the Library has acquired numerous new works in the history of medicine and expanded its scope to include biomedical ethics and medical humanities. Presently, the Library holds approximately 45,000 monographs, 1800 bound serials, and numerous manuscripts.