Responding to a plea from Montana citizens for an institution of higher education in central or eastern Montana, the fifth unit of the Montana University System -- Eastern Montana State Normal School -- was established March 12, 1927, with Dr. Lynn B. McMullen named the first president. At the time, the population of Billings was 15,000. Although the institution was granted several acres of land nestled under the famous Rimrocks, classes had to be held in downtown Billings until the first building, McMullen Hall, was completed in December, 1935.

At first, the Normal School was authorized to offer a two-year certification program for elementary teachers. It enrolled 149 students (140 women, 9 men), with a faculty of 14.

Between 1927 and 1945, commencement exercises were held quarterly. Montana Governor J. E. Erickson gave the commencement to the first three graduates (one of whom was 52 years of age) in March, 1928.

Over the first 16 years, enrollment averaged 175 students, but, with the onset of WWII, enrollment fell to 50 (women only) in 1945. All athletic and many social activities came to a halt, but resumed with enthusiasm after the war.

In 1949, the Normal School changed its name to Eastern Montana College of Education. Enrollment broke the 1,000 mark in 1958. In 1964, enrollment reached 2,162, and the students were asked to design a campus flag. The original flag featured yellow lettering on a field of blue surrounding the official seal of the school. The motto, "Education is Life" continues to challenge today's students.

In 1965, the institution's name was changed to Eastern Montana College. Enrollment surpassed 3,000 in 1967, and in that same year the College of Liberal Arts was established. EMC's enrollment broke the 4,000 mark in the early 1970s, and in 1979 the Montana University System (MUS) Board of Regents gave their final approval for the establishment of the College of Business. In 1983, the University recorded its largest enrollment -- 4,424.

In 1994, the MUS was restructured. Eastern Montana College changed its name for the third time on July 1, 1995, becoming Montana State University Billings. As a result of the reorganization, all campuses governed by the Board of Regents, including all former vocational-technical centers, were aligned with either Montana State University or the University of Montana. MSU Billings affiliated with Montana State University - Bozeman. The former Billings Vocational Technical Center was merged fully into MSU Billings and became MSU Billings College of Technology. In the spring of 2004 the university formally launched its fifth college - the College of Health Professions and Science.

The College of Technology received another name change in June 2012 when the MUS Board of Regents approved changing its name to City College at Montana State University Billings.  The purpose of the name change was to help increase the awareness of the expanded mission of the two-year campuses across the state of Montana; which included the traditional workforce training programs (career and technical education) as well as transfer education opportunities. 

Dr. Ronald P. Sexton was appointed the ninth Chief Executive Officer of MSU Billings in 1995. He became the first person to hold the title of Chancellor of the University. Dr. Rolf Groseth was appointed to the position in 2010, followed by Mark Nook in 2014, and Dr. Daniel Edelman in 2018. In 2021, Dr. Stefani Hicswa became the first female chancellor at MSUB.  

In 2019 the university received board of regents approval to rename two of its five colleges. The College of Allied Health Professions changed its name to the College of Health Professions and Science (CHPS), and what was once the College of Liberal Arts became the College of Liberal Arts & Social Sciences (CLASS). 

Today, MSU Billings is a comprehensive, regional University dedicated to delivering a transformative education that empowers students from diverse backgrounds to succeed. Eighty-six percent -- well above the national average -- of its outstanding faculty hold the highest degrees in their fields.

Spread over 98 acres, MSU Billings has 16 buildings, employs more than 900 full-time and part-time people, and is the fourth largest employer in Yellowstone County, with an annual payroll in excess of $18 million. With an enrollment in excess of 4,200, this campus is the third largest unit in the Montana University System. It offers a wide range of academic programs -- from licenses and certificates to associate, bachelor's, and master's degrees. Other academic programs -- unique in the Montana University System -- are offered in the areas of human services, special education, and rehabilitation.

Public service activities of the University include the Montana Center for Inclusive Education, established in 1947, and KEMC/KBMC Public Radio which was originally licensed to the University in the early 1970s.