Mabel May was part of a large family in Montreal, and, although delayed by her family duties, she began her training in 1902 at the Art Association of Montreal, where she studied with William Brymner. In 1912, she traveled to Paris with fellow artist Emily Coonan, with trips to England and Scotland. She returned to Canada in 1913, opening a studio in Montreal. Summers were spent painting at the family cottage in Hudson and she painted with her friends in the Eastern Townships, New England and Baie-Saint-Paul in the Lower St. Lawrence area. She won the AAM's Jessie Dow Award in 1914 and 1918, and in 1915 became a member of the Royal Canadian Academy. Hired by the Canadian War Memorials Fund in 1918 to memorialize the war effort, May documented women involved in munitions work. May's early work was influenced by Impressionism.
In 1920, May became a founding member of the Beaver Hall Group in Montreal, and shared a studio with Lilias Torrance Newton at the Beaver Hall Hill space. She exhibited in the two Beaver Hall exhibitions in 1921 and 1922. Her landscapes after 1920 show the influence of the Group of Seven - with a fine understanding of light and atmosphere, and strong forms depicted with confident brush-strokes. Group member A.Y. Jackson was involved with the Beaver Hall Group, and she maintained ties with Jackson and other members of this group such as Newton throughout her life.

May was an active exhibitor, and participated in the Art Association of Montreal's spring exhibitions from 1910 to 1967, and in the exhibitions of the Royal Canadian Academy of Arts from 1910 to 1952. She exhibited with the Group of Seven in Toronto in 1928, 1930 and 1931. A founding member of the Canadian Group of Painters in 1933, she also exhibited with them. From 1938 to 1947 she showed her work with a group called Le Caveau. The National Gallery recognized her work early on, acquiring four of her works between 1913 and 1924, followed by more later.

The Depression of the 1930s brought challenges - May's family cottage was sold, and to support herself, she began to teach art classes in 1936 at Elmwood, a private girl's school near Ottawa, staying until 1947. She also taught art classes for children at the National Gallery of Canada from 1937 to 1947.

May also exhibited internationally in group shows, including the influential British Empire Exhibition in Wembley, England in 1924. In 1927 she exhibited at the Musée du Jeu de Paume in Paris, in 1930 at the Corcoran Gallery of Art in Washington, DC, in 1938 in A Century of Canadian Art at the Tate Gallery in London, in 1939 at the New York World's Fair, 1944 in the Museu Nacional de Belas Artes, Rio de Janeiro, Brazil and in 1947 at the Riverside Museum in New York.

In 1948 she returned to Montreal, giving private art lessons until 1950, when she moved to Vancouver to be near her sisters. In 1952 she had a solo exhibition at the Vancouver Art Gallery. She died in Vancouver in 1971.