Returning to the United States after medical school, Mitchill completed law school.
Mitchill taught chemistry, botany, and natural history at Columbia College from 1792 until 1801 and was a founding editor of The Medical Repository, the first medical journal in the United States. In addition to his Columbia lectures on botany, zoology, and mineralogy, Mitchill collected, identified, and classified many plants and animals, particularly aquatic organisms. From 1807 to 1826, he taught at the College of Physicians and Surgeons of New York and then helped organize the short-lived Rutgers Medical College of New Jersey, which he served as vice president until 1830.
While at Columbia, Mitchill developed a fallacious theory of disease, which however resulted in his promotion of personal hygiene and improved sanitation.
Mitchill served in the New York State Assembly in 1791 and again in 1798 and was then elected as a Democratic-Republican to the United States House of Representatives, serving from 1801 until his resignation on November 22, 1804. In November 1804, Mitchill was elected a United States. Senator from New York to fill the vacancy caused by the resignation of John Armstrong, and served from November 23, 1804, to March 4, 1809.
He then served again in the House of Representatives from December 4, 1810, to March 4, 1813. Mitchill suggested renaming the United States of America Fredonia, combining the English "freedom" with a Latinate ending.
Although the suggestion was not seriously considered, some towns adopted the name, including Fredonia, New New York
Some freebooters even established a short-lived republic under that name in Texas in the late 1820s. Mitchill was a man of "irrepressible energies..polyglot enthusiasms.. distinguished eccentricities" who was not "a man afraid to speak out loud about the loves of plants and animals. Indeed, he was not a man afraid to speak out loud on most any topic.
In the early nineteenth century, Mitchill was New York"s "most publicly universal gentleman..a man known variously as the "living encyclopedia," as a "stalking library," and (to his admired Jefferson) as the "Congressional Dictionary."" "Once described as a "chaos of knowledge," Mitchill was generally more admired for his encyclopedic breadth of understanding than for much originality of thought." As a personality he was affable but also egotistical and pedantic.
Mitchill enjoyed popularizing scientific knowledge and promoting practical applications of scientific inquiry.
American Academy of Arts and Sciences]
Mitchill was elected a member of the American Antiquarian Society in 1814. Mitchill strongly endorsed the building of the Erie Canal, sponsored by his friend and political ally DeWitt Clinton. They were both members of the short-lived New-York Institution.