Union Hospital, Tongji Medical College, Huazhong University of Science and Technology was founded on September 8, 1866 by Griffith John from the U.K. Originally named Hankow Renji Hospital with the meaning of "healing the world with love and uniting the people with sincerity", the Hospital was located at Houhualouju Alley (now Jiaotong Alley) and was equipped with 2 wards, 15 beds and 1 part-time doctor upon its establishment.

After its establishment, Renji Hospital kept expanding. In 1878, a new location was opened at Guangnan Foreign Firm on Taiping Road (now the site of Siming Bank on Jianghan Road), and was expanded several times later to accommodate more patients. In 1891, Margaret Memorial Hospital was built and named in memory of Griffith John's late wife. From then on, Renji Hospital had a women's department.

As its business grew, Renji Hospital's wards could no longer meet the increasing medical needs. After discussion among the Hospital's board of directors and persons in charge, preparations were started for the construction of a new hospital on Hankow Ximan Road (later renamed Zhongzheng Road, which is also the current site of Union Hospital on Jiefang Avenue). At the same time, the Hospital was actively seeking partners to build up the strength of the new hospital. In 1926, Renji Hospital, together with Pu'ai Hospital, formed Hankow Hospital Association and Hankow Union Hospital. After the completion of the construction in early 1928, the Hospital was formally opened on April 4 with an unveiling ceremony. Thomas Gillison, President of the former Renji Hospital, served as the first President of Hankow Union Hospital. At the gate of the Hospital, three signs were hung, with “Hankow Union Hospital” right above the gate, the “First Hospital of Renji” on the right and the “Second Branch of Pu’ai” on the left sides.

In the meantime, the Hospital actively developed medical education. In 1902, Thomas Gillison, President of Renji Hospital, and physician Percy Lonsdale McAll co-founded Union Medical College, which was the first medical school of higher education established in Hankow. In 1928, Boyi Health Technical College founded by George Hadden, a British doctor, was moved into Hankow Union Hospital to set up its headquarters. Moreover, the former Renji Hospital and the nursing school set up in the Pu'ai Hospital jointly established Union Nursing School, which later became Puren Nursing School.

In 1931, the floods hit Wuhan, causing damage to part of the Hospital's buildings. To carry out disaster relief as well as disease prevention and treatment, the Hospital, in cooperation with Shanghai International Flood Relief Committee and China Flood Relief Committee, rented Hannah Moller——a coal ship——and converted it into a hospital ship. At the same time, temporary medical centers were also set up to accommodate and treat patients. After the floods, reconstruction work was carried out while the Hospital was still in service. By the end of 1932, restoration of main buildings was completed and the Hospital resumed its operations.

In 1950, the Hospital was renamed Hankow Union Hospital (Teaching Hospital of Tongji Medical College of Wuhan University), directly under the leadership of Zhongnan Ministry of Health.

With the relocation of the Medical College of Shanghai Tongji University to Wuhan and the changes of the university name, the Hospital was successively renamed Hankow Union Hospital (Teaching Hospital of Zhongnan Tongji Medical College) (October 1954-June 1955), The First Affiliated Hospital of Zhongnan Tongji Medical College (June 1955-August 1955), The First Affiliated Hospital of Wuhan Medical College (August 1955-May 1985), Union Hospital, Wuhan Medical College (May 1985-July 1985), and Union Hospital, Tongji Medical University (July 1985-May 2000). In 1989, Tongji Medical University was placed under the jurisdiction of the National Health Commission (formerly the Ministry of Health), and the Hospital became a hospital under the jurisdiction of National Health Commission.

In May 2000, Tongji Medical University merged with Huazhong University of Technology and Wuhan Urban Construction College to form Huazhong University of Science and Technology. From then on, the Hospital was renamed Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Through the unremitting efforts of Union people for several generations, the Hospital has developed into a modern comprehensive class-A tertiary hospital integrating medical treatment, teaching and scientific research. In 2019, the comprehensive strength of Union Hospital has entered the top ten in the country.