[2] The year after it was established, the hospital entered into an agreement with the Harris County Commissioners Court to care for the city's indigent patients.

[3] The hospital earned a great deal of community support due to the care it provided to victims of an 1891 smallpox outbreak.

[8] In 1920, an article in the Texas State Journal of Medicine mentioned that it had a strong nursing school and characterized the hospital as "an institution second to none in the south".

An account in the Annals of St. Joseph's Infirmary indicates that the hospital's emergency room treated more than 50 people injured in the disaster.

[14] The hospital's plastic surgery chief, Dr. Thomas Cronin, met with representatives from Dow Corning in 1961 to discuss alternatives to sponge implants for breast augmentation.

Dr. Cronin and his plastic surgery resident Frank Gerow are credited with developing silicone gel implants during those meetings with the company.

[16] Before the establishment of Texas Children's Hospital in 1954, St. Joseph had a clinical affiliation with the Department of Pediatrics at Baylor College of Medicine.

He theorized that uterine contractions (absent in many babies born by C-section) helped to prepare a fetus for the task of breathing.

In 1998, the hospital completed a three-year, $50 million expansion project, including a new pavilion chiefly designed for outpatient care.

In June 2008, HPA abruptly closed both locations of its other Houston hospital, River Oaks Medical Center.

[26] St. Joseph has been designated a Level III trauma center by the Texas Department of State Health Services.

[28][29] In August 2015, an unarmed patient experiencing a psychotic episode was shot by off-duty police officers providing security services at the hospital.

[30][31] However, in January 2016, SJMC and CMS reached an agreement allowing the hospital to remain funded while certain deficiencies were addressed.

In October 2017, the hospital changed ownership when Iasis Healthcare was acquired by Steward Health Care.

[33]On May 5, 2024, The Wall Street Journal reported that Steward Health Care was expected to file for Chapter 11 bankruptcy protection within the coming days, blaming rising costs, insufficient revenue and cash crunches as part of the decision.