In its early years, the university operated as an academy and junior college. In 1925, it became a four-year liberal arts college. The descendants of 19th century settlers in Minnesota and Wisconsin thus received a classical education from a highly educated faculty composed primarily of diocesan clergy. The students of the early decades became religious, professional, and business leaders in their communities.

The Institute of the Brothers of the Christian Schools, an international Catholic teaching order founded in France in 1680 by Saint John Baptist de La Salle, purchased Saint Mary's College from the Diocese of Winona in 1933. Soon thereafter, the university obtained formal accreditation of its bachelor's degree programs by the North Central Association of Colleges and Schools. Enrollment increased from 200 to 500 students over the next 15 years, aided by an influx of graduates from De La Salle Christian Brothers' high schools in Minneapolis, Saint Paul, Chicago, Kansas City, and St. Louis.

The Saint Mary's College curriculum, combining the traditional liberal arts and sciences with career-related studies, served the interests of both students and faculty in pursuing an integrated liberal and career education. Major programs included accounting, business administration, preparation of secondary-school teachers, and strong pre-professional majors in natural and social sciences, mathematics, law, medicine, theology, philosophy, and the humanities. All students completed a general education in the liberal arts in addition to their chosen major. These historical components of Saint Mary's College exist in today's curriculum, alongside the career-related applications that have evolved in recent years.

In a national study conducted during the 1980s, Saint Mary's University achieved a ranking in the top 15% nationally in the proportion of its graduates who later went on to earn a doctoral degree.

In the late 1950s and throughout the 1960s, when enrollment reached the 1,000 mark, the college expanded its physical facilities significantly, especially to accommodate housing needs for the high representation of students (85%) electing to live on campus.

The Catholic religious developments embodied in Vatican Council II in the mid-1960s, as well as the social movements of that decade, transformed Saint Mary's College. Between 1968 and 1974, the college experienced one of the greatest periods of change in its history:

1. establishment of an independent Board of Trustees, all but the president being from outside the university;
2. clear separation of college administration from the district administration of the De La Salle Christian Brothers;
3. revision of faculty and student body governance;
4. a decision to become a coeducational institution in 1969, starting with a very small class of women; subsequently to the achievement of a complete balanced mix of genders within the student body;
5. declining numbers of seminarians and Brothers in the student body;
6. shift in perception from "student" to "young adult" status, and
7. expansion of the curriculum. By 1980, enrollment had surpassed 1,200 undergraduates and 200 master degree students.

Constructed during this decade were the Ice Arena (1986), Performance Center, including Figliulo Recital Hall and Joseph Page Theatre (1987), Brother Charles Hall science addition (1987), Gilmore Creek Residence (1989), and Christian Brothers Residence (1989). Extensive renovation also took place. The Saint Thomas More Chapel, art and music facilities, and most classrooms and residence halls were remodeled.

From the mid-1980s to the present time, simultaneous with the elimination of all deferred maintenance to the facilities, the addition of new facilities and the renovation of existing campus buildings, vigorous change and growth took place within the academic and in every other area of Saint Mary's.

Major curricular changes occurring since the mid-1980s were the development of a completely new core curriculum, the introduction, and eventual expansion of the Lasallian Honors Program, the establishment of the De La Salle Language Institute and the introduction of the Path to Academic Success program. Foreign study centers were established, expanding international educational opportunities to greater numbers of the traditional undergraduate student body.

The Hendrickson Institute for Ethical Leadership, along with new degree programs at both the undergraduate and graduate levels, were all additions during this time, bringing greater depth and outreach to the mission of Saint Mary's University.

The academic administration of the College was divided into schools in order to more effectively concentrate on the wide range of offerings being made to an increasingly diverse student body. In addition to these many changes, a new campus was established in Nairobi, Kenya, offering a Bachelor's degree in education and a Master's degree in African Studies. In 1995, Saint Mary's College was renamed Saint Mary's University of Minnesota.

During the 1990s, the Winona campus saw the construction of the Recreation and Athletic Center (1994) featuring the Gostomski Fieldhouse and Jul Gernes Pool, McEnery Center library addition (1994), Pines Hall Residence (1995), Hendrickson Center addition to Saint Mary's Hall (1996), The Heights academic building (1997), and Hillside Hall Residence (2001).

In 2002, Saint Mary's purchased the campus of the former College of Saint Teresa in Winona. Several buildings were subsequently sold to Winona State University and Cotter High School. SMU retains ownership of the Chapel of Our Lady of the Angels, Alverna Center, the 360 Vila St. building, and Válencia Arts Center.

The Regan Lobby of the ice arena was added in 2004, and in 2008, the Winona campus athletic fields were transformed by a new track and soccer complex.
Graduate and Professional Education

From the 1970s to mid-1980s, Saint Mary’s offered graduate programs in Saint Paul with small groups of students at Cretin High School, then at Saint John's Hospital.

In 1984, the university expanded its offerings to meet a more diverse population with new educational goals. Night and weekend classes were made available to accommodate the many students who also work full-time. Vigorous growth began with the decision to move core centers for graduate studies to a campus at 2500 Park Avenue in Minneapolis and a center in Rochester, Minn. Graduate programs were expanded on the Winona campus, and centers were established in Apple Valley, Minn. along with the Partners in Higher Education, and in Minnetonka and Oakdale, Minn.

Courses are now delivered at more than 100 on- and off-campus locations in the metropolitan area, greater Minnesota and Wisconsin, Jamaica, and Nairobi, Kenya. Program levels include bachelor completion, certificate, specialist, master degree and doctoral. The SGPP serves more than 4,300 adult learners, making it one of the largest graduate schools in Minnesota.

In 2007, the reorganized Schools of Graduate and Professional Programs was divided into the Graduate School of Education, the Graduate School of Business and Technology, the Graduate School of Health and Human Services, and the School of Professional Programs. The SGPP also gained a new advisory Board of Regents.

The University is true to its Lasallian heritage in Saint John Baptist de La Salle's belief in meeting the needs of the people of the times. Saint Mary's continues to carry out this integral part of our mission. It strives at the same time to remain a university that is attentive to unique individuals with varying psychological, social, physical and spiritual needs. This has been a hallmark of this university's success and a critical dimension which seems most appropriate in these ever-changing, conflicted times.

There are many positive opportunities on the horizon for the university. Saint Mary's University received its continued accreditation from the Higher Learning Commission of the North Central Association of Colleges and Schools in 2007 until 2017. The university continues to be increasingly attractive to our diverse audience of students. New and exciting possibilities await us on the horizon and we welcome them in our desire to continue to refine and increase the quality and degree of excellence our educational offerings can provide for every individual member of our academic community.