Metropolitan Hospital Center was founded in September 1875, the same year it began its affiliation with the New York Homeopathic Medical College (now known as the New York Medical College). This relationship has become the oldest medical college-hospital affiliation in the United States.

Metropolitan’s first home was the Homeopathic Hospital, established by the New York City Department of Public Charities and Correction, on Ward's Island in the East River. Housed in a building originally constructed in 1867 for the Inebriate Asylum, it was later known as the Ward's Island Hospital.

In 1894, the hospital moved to Blackwell's Island (later known as Welfare Island and currently Roosevelt Island). It occupied the former New York City Asylum for the Insane and was renamed Metropolitan Hospital.

The hospital moved to its present location in East Harlem in 1955, into two newly constructed buildings now dedicated to inpatient and outpatient services. Metropolitan was officially designated a Hospital Center in 1965. A year later, the hospital added its Mental Health Building, an adjoining 14-story pavilion housing the hospital’s psychiatric services.

In 1981, the NYC Health and Hospitals Corporation established a managed care demonstration project, Metropolitan Health Plan. It was one of the first HMOs in a public hospital and later became known as MetroPlus Health Plan.

In 2006, Metropolitan received designation as an official Stroke Center from the NY State Department of Health, one of the first in Manhattan and the very first in East Harlem.