Sunnybrook has made surgical breakthroughs in its history, including the world's first non-invasive opening of the blood–brain barrier being performed in 2015.

The Collegiate Gothic building had originally been the site of the National Cash Register Company Factory in 1913 by the architects Page and Warrington,[5] but it was converted for use as a military hospital in 1919 to house soldiers injured during World War I as well as some veterans disabled in the Boer War and the Fenian Raids.

The influx of disabled soldiers returning from World War II led to overcrowding and required a new hospital.

[6] The original site was demolished in 1981 and replaced by Christie Gardens Apartments and Care Facility, at 600 Melita Crescent.

[6] Joseph and Alice M. Kilgour, a wealthy Toronto couple, purchased 154 acres (62.3 ha) in the nearby town of Leaside and created Sunnybrook Farm, where they raised horses and hosted fox hunts.

In 1928, after Joseph's death, Alice Kilgour donated Sunnybrook Farm to the City of Toronto in his memory for use as a public park.

[9] On July 1, 2012, Sunnybrook and St. John's Rehab Hospital, which had complementary programs and services, voluntarily merged to provide a continuum of care from acute injury or illness to rehabilitation and recovery.

[9] As of 2016, Sunnybrook maintains three campuses, with its main campus (Bayview) on Bayview Avenue in North York, the satellite Holland Centre (orthopaedic and arthritic care) on Wellesley Street East, and St. John's Rehab on Cummer Avenue.

The program's main areas of focus include stroke, dementias and mood and anxiety disorders.

[16] The program focuses on musculoskeletal injury, total joint replacement and major biological restoration.

[19] In 2017, the program opened North America's first pregnancy clinic for women with physical mobility disabilities.

[33] The Integrated Community Program was established to ensure that the transition from hospital to the next step is one where everyone involved is both informed and engaged.

A helicopter pad (TC LID: CNY8) is located at the east end of the hospital grounds, as well as on the rooftop of the building’s M-wing.

Sunnybrook Hospital was from 2001 to 2003 the site of Ontario's first private for-profit cancer clinic to be created since the inception of Medicare.

[38][39] The Holland Centre consists of the Orthopaedic Program located in Downtown Toronto, on 43 Wellesley Street East.