Saint Joseph Hospital was started when a handful of sisters, with $9 in their pockets, set forth from Leavenworth, Kansas to Denver, Colorado in order to care for the poor and ill. What became known as Sisters of Charity at Leavenworth (SCL) started with a small cottage, and then in September 1873, through donations and begging, opened the first hospital at 1421 Arapahoe Avenue.

Soon the sisters found themselves running low on space, and some time in 1874, they moved to a larger structure near the red light district of Denver, at 26th and Holladay (later Market St.).

The name was changed to Saint Joseph Hospital in 1876 - partially in honour of bishop Joseph Machebeuf - when the Sisters moved yet again, this time further east of downtown, at 18th Avenue and Humboldt Street on land donated to them by territorial Governor William Gilpin.

Led by flour baron John K. Mullen, the people of Denver raised $10,000 for this building with a "gigantic city-wide bazaar," and a "monster" euchre (whist) party, planned by Margaret Brown.

In 2014, Saint Joseph Hospital completed its current facility located at 1375 E. 19th Avenue and Downing Street in Denver.