Mabel Lockerby was born in Montreal into a family that belonged to the Anglo-Protestant elite. After her father died, she took over responsibility for her family. Lockerby had the freedom to paint, and was an outspoken and unconventional personality. She studied at the Art Association of Montreal for about nine years, starting around 1902, and was instructed by William Brymner and Maurice Cullen. Unlike many of her contemporaries, she did not study abroad. Around 1914 she began showing in the Art Association of Montreal's exhibitions and was a regular participant there and in the Royal Canadian Academy annual exhibitions.

In 1920 Lockerby became a founding member of Montreal's Beaver Hall Group, and when the group was formally disbanded, she continued to exhibit with them. In 1941 she participated in a four-woman show at the Art Gallery of Toronto, in 1950 she was part of a six-woman show at the Montreal Museum of Fine Arts and in 1952 in a three-woman show at the Montreal Museum of Fine Arts, all of which included Beaver Hall painters. She went on sketching trips with fellow members Prudence Heward, Kathleen Morris and Sarah Robertson. Lockerby was known for street scenes, figurative works and landscapes, and for her strong sense of composition and form.

Lockerby's extensive exhibition history also included international showings - she was included in the 1924 to 1925 British Wembley Exhibition in England, the Exposition d'art Canadien at the Musée du Jeu de Paume in Paris in 1927, the Corcoran Gallery in Washington DC in 1930, Buenos Aires in 1931, the Royal Institute Galleries in London and the important exhibition A Century of Canadian Art in 1938 at the Tate Gallery in London. In 1939 her work was shown at the New York World's Fair and in 1944 at the Yale University Art Gallery and at the Museu Nacional de Belas Artes, Rio de Janeiro.

Lockerby was also affiliated with art societies, and in 1939 was elected to the Canadian Group of Painters, and in 1940 to the Contemporary Arts Society of Montreal, and she participated in their exhibitions. Lockerby's last exhibition was at the Art Association of Montreal in 1956, and she died in Montreal in 1976.