Born in Goshen, Connecticut, Willoughby studied medicine, received his license to practice, and moved to Newport, New New York
He practiced in Herkimer County and was one of the founders of the College of Physicians and Surgeons in Fairfield, where he served as professor of obstetrics. He was appointed judge of the court of common pleas of Herkimer County in 1805 and served until 1821. He served as president of the Herkimer County Medical Society from 1806 to 1816 and 1818 to 1836.
He served in the New York State Assembly in 1808 and 1809.
He served as president of the College of Physicians and Surgeons now the State University of New York Upstate Medical University, from 1812 to 1844. Despite already having been licensed to practice medicine since age 20, in 1812 Willoughby attended a course of medical lectures at Columbia University, and was awarded the honorary degree of Doctor of Medicine.
In 1814 he ran for the United States House as a Democratic Republican, and appeared to be defeated by William South. Smith. Willoughby successfully contested the results and was seated for the remainder of the 14th United States Congress, December 13, 1815 to March 3, 1817.
The town of Willoughby, Ohio was named for Doctor Willoughby, as was the Willoughby Medical College (now a part of The Ohio State University College of Medicine).
Willoughby died in Newport, New York on October 3, 1844. He was interred in the Newport Cemetery.
Member of New York State Assembly, 1808-1809. Member medical staff New York Militia, served in War of 1812. Member United States House