[8] Located in Western New York on the Lower West Side of the City of Buffalo, the campus is in an urban setting a few blocks from the Peace Bridge on the Canadian border.

[10] CannonDesign was retained to develop D'Youville's most recent campus Master Plan and the major priorities of that planning effort are focused toward revitalizing the campus in ways that improve its connection to the Buffalo Olmsted Park System, as well as beautifying the Lower West Side of Buffalo and improving the connectivity and traffic flow through the local neighborhoods.

[14] Her desire to serve those in need went against the social conventions of Marguerite’s generation, leading her and three other women to establish the Sisters of Charity in 1737 — a service-oriented organization commonly known as the Grey Nuns.

The institution was incorporated and filed in the Secretary of State's Office on February 13, 1865, under the name, "The Holy Angels Infirmary Academy and Industrial School for Benevolent, Charitable, and Scientific Purposes".

D'Youville was initially founded as an institution focused on education and the liberal arts, with particular emphasis on women, students of immigrant status, and populations that lived in under-resourced communities.

There were excellent courses in languages, in science, mathematics and history taught by superior professors...certainly none in sewing or etiquette.”[15]Over the next several decades objectives of study emphasized the teaching professions and intellectual interests guided students toward extra-curricular activities focusing on dance, music, drama, language, and political debate.

As the U.S. economy bounced back from the great depression in the 1950s, D'Youville's enrollment began increasing and stimulated need for a larger campus.

[30] The purchase of an old laundry mat building adjacent to campus in 1978 was the first evidence that D'Youville's financial situation had stabilized following the co-ed transition.

[15] In 1984, President Ronald Reagan spoke at D'Youville during a campaign event with the Italian and Polish communities near the end of his first term in office[31] after participating in the dedication of the Santa Maria Towers.

[32] This event is referenced as the only visit that President Reagan ever made to Buffalo, New York,[32] and as a result, a memorial service with residents and community leaders was also held at D'Youville 20 years later when he died in 2004.

[33] A second period of stability and growth occurred around the turn of the century, largely driven by the growing number of Canadian students attracted by a favorable currency exchange rate.

[15] D'Youville enrollment growth was also attributed to the addition of masters and professional health professions degree programs in the 1980s, which expanded the institution's focus beyond a liberal arts college.

[36] The Dobson Athletic Complex[37] and the Dr. Charles and Mary Schweitzer Bauer School of Arts, Science and Education were built in 2015.

[39] The university opened a Health Professions Hub building in June 2021, which includes an inter-professional clinic and laboratory, pharmacy, rehabilitation gym, simulation labs, dietetics kitchen, and events space.

[49] The Health Profession Hub was recognized by the American Institute of Architects (AIA) Buffalo/Western New York with the 2021 highest design honor award.

[60] The shift to a 4-day workweek started as a 6 month trial technology driven health and wellness initiative, and was then made permanent.

[23] The current 4-story Montante Family Library opened in 1999, after a $10 million[82] renovation of the previous Holy Angels School building.

[23] In 2021, D'Youville was ranked as #299-391 among national universities and #113 in top performers on social mobility by U.S. News & World Report.

[84] D'Youville was approved July 2020 to compete at the NCAA Division II level, as a new provisional member of the East Coast Conference (ECC) beginning in the 2020–21 season.

[88] The athletic department announced the addition of men's lacrosse and esports as new sports beginning in 2021–22, bringing the institution to have 16 intercollegiate programs.

The D'Youville Magazine was first published in 1910 and ran through the 1960s, primarily serving as an outlet for student papers as well as other literary publications and commentary.

[48] A capital campaign was led by Edward Kavinoky, the board of trustees chairman at the time, to renovate the space and extend the stage to support theatre productions.

[48] The Kavinoky Theatre was renovated again to have new paint, carpet and seating in 2020, partially sponsored by the New York State Council on the Arts.

[93] Recently, the Kavinoky Theatre has produced shows such as To Kill a Mocking Bird,[94] Hairspray,[95] 1984,[96] Spamalot,[97] and Sweeny Todd.

[100] The statue plaque highlights d'Youville's life span (1701-1771) and her title "Mother of Universal Charity,"[101] which was given to her by Pope John XXIII in 1959.

[102] On October 11, 2019, in alignment to National Coming Out Day for the LGBTQ+ community, D'Youville host an inclusivity event named "From the closet to the sidewalk" and unveiled the As is mural by Casey Millbrand.

[104] On June 19, 2020, in alignment to the Juneteenth holiday celebration, D'Youville unveiled the Black Matter is Life mural by Maxx Moses.

[105] August 12, 2021, to finalize the Health Professions Hub building, the Tree of Y mural was painted on the facade by Maya Hayuk.