The Central Chiropractic College was founded in 1922 by Palmer graduates Dr. C.S. Cleveland Sr.; Dr. Ruth R. Cleveland; and Dr. Perl B. Griffin–enrolling three students in its first class, and graduating its first doctor of chiropractic in 1924. The college was incorporated December 1922 as a non-profit, "benevolent association," which gives it the distinction of being the oldest surviving and continuously operating non-profit chiropractic college. The Articles of Incorporation were amended in 1924 to change the name of the institution to Cleveland Chiropractic College.

The original campus, located at 436 Prospect Avenue (photo) just south of the Missouri River, was a converted residence that doubled as college facility and home for Dr. Carl Sr., Dr. Ruth, and young son Carl S. Cleveland Jr. The kitchens were converted to chemistry and human dissection laboratories, with the lower living area serving as the patient clinic. The turret windows at the front of the house allowed the occupants to observe any caller at the front door. This precaution was deemed essential because many early chiropractors were arrested for the unlicensed practice of medicine prior to the 1927 passage of Missouri’s chiropractic law.

Dr. C.S. Cleveland Sr., the first president, was a pioneer in the field of chiropractic and chiropractic education. He served as a vocal activist and provided expert testimony, forming the basis for the passage of the Chiropractic Practice Act that legally defined the profession as a separate and distinct healing art in the state of Missouri. From the beginning, Dr. Cleveland Sr. emphasized early hands-on technique, focusing on specificity in spinal analysis and adjustive procedure, combined with instruction in x-ray analysis at a level beyond that of competing institutions of the time.

Dr. Cleveland Sr. was respected for his oratory and acknowledged for his instruction in the dynamic thrust procedure of the full spine recoil adjustive technique. He was a frequent lecturer at the Palmer School and other colleges. Even as competitors in chiropractic education, Dr. Cleveland Sr. and Dr. Ruth Cleveland maintained close relationships with their alma mater, the Palmer School, and sustained a longtime friendship with the Drs. B.J. and Mable Palmer.

In 1951, Dr. Cleveland Sr. relocated to Los Angeles to take leadership of the Ratledge College.