Miami witnessed population increase during the 1940s, creating a demand for more accessible healthcare. To address this need, the diocese of St. Augustine, which oversaw all of Florida, acquired a significant piece of land along Biscayne Bay. The local community supported the establishment of a new hospital, contributing through various fundraising efforts such as door-to-door collections and public appeals in places like schools and movie theaters.

Construction of the hospital began in 1946, and on December 18, 1950, HCA Florida Mercy Hospital officially opened with 125 beds. The Sisters of St. Joseph of St. Augustine assumed operational responsibility from the Diocese in 1966. They played a pivotal role in the hospital's management and staffing, demonstrating their leadership in nursing and administration during a period when these roles were predominantly held by men.

From its inception, Mercy Hospital has been committed to providing compassionate, high-quality care rooted in the principles of Catholic Healthcare Ministries.

In 1960, it became the first hospital in Miami to open its doors to Cuban exile physicians. The next year, Mercy Hospital offered free medical care to members of the Bay of Pigs Brigade.

Despite a change in ownership in 2011, Mercy Hospital remains dedicated to its mission of patient-centered care. Several Sisters continue to serve on the hospital’s board, upholding its faith-based approach to healthcare. Mass is celebrated twice daily in English and Spanish, emphasizing the hospital's commitment to their patients’ spiritual well-being.