Its foundation is accredited to Mother Xavier Ross, who traveled to Leavenworth at the invitation of Bishop Jean Baptiste Miege in 1858.

[4] Shortly after her arrival, an orphanage for African-American children, an academy for girls, and a program for the visitation of prisoners at the nearby Fort Leavenworth was set up.

The tower added to the size of the hospital considerably, bringing it to seven-stories tall, and solidified its position as the largest medical center between Salt Lake City and Denver.

St. Mary's Medical Center is the tallest building in the city of Grand Junction, standing at 146 ft (45 m) tall.

The hospital has a helipad on its tower, and works in conjunction with CareFLIGHT of the Rockies to provide air transportation for critical patients in the region[10] The Family Medicine Residency program at St. Mary's was founded in 1979.