The first medical education in Colorado began with the establishment, on June 9, 1881, of a Medical Department of the University of Denver and Colorado Seminary. The Department was composed of 15 members of the Denver medical profession and one layman. Five students graduated in 1883, at which time there were 16 undergraduates, including one woman. The governance of the department was altered by its incorporation, on August 10, 1899, as The Denver College of Medicine through an agreement with the College of Medicine and the University of Denver, Colorado Seminary.

In the meantime, in 1877, another group of Denver doctors had started the Gross Medical College . In 1902, the boards of the two medical schools agreed to merge. The merger was completed in 1903, and as part of the agreement, the University of Denver agreed to provide facilities for the Denver and Gross College of Medicine in the Haish Building, located at 14th and Arapahoe Streets, Denver. In 1907, a new building was constructed for the Medical College for use as a dispensary and clinic.

The era of small, independent, medical colleges was fading. There was a call for evaluating and regulating medical education, led by the Council on Medical Education of the American Medical Association and Association of American Medical Colleges, and the Carnegie Foundation for the Advancement of Teaching. As early as 1908 there was talk of merging The Denver and Gross College with the University of Colorado Medical Department. In 1909 a major report on the state of medical education in the United States was commissioned. The Flexner Report, as it was called after its head researcher, Abraham Flexnor, called for a reorganization of medical education. In its evaluation of The Denver and Gross College of Medicine, the Flexner criticized the fact that the School's affiliation with the University of Denver was on a six month basis. The report criticized the facilities and the manner in which interaction with area hospitals was managed. The Flexner report also recommended that The Denver and Gross College consolidate with the University of Colorado School so that the resulting school could benefit from state appropriations for the medical school.

In response to the Flexner report, the executive board of the Denver and Gross College demanded that the trustees of the University of Denver either grant the medical department finances to sustain a modern Class A institution or approve a merger with the University of Colorado. An agreement was reached in 1910, and the consolidation of the schools was effective January 1911.