Born Margaret MacDonald at Tipton, Staffordshire, she studied at Glasgow School of Art along with her sister, Frances. There she met her future husband, the architect and designer Charles Rennie Mackintosh. Together with fellow student Herbert MacNair (whom Frances married), they made up an influential group known as the "Glasgow Four". Following her marriage to Charles Mackintosh in 1900, Margaret continued painting watercolours and collaborating with her husband in decorative work and design, at Glasgow and at London, to which city they moved in 1914.
By 1923, however, Margaret was no longer painting. The Mackintoshes took an extended holiday in France, but were obliged by Charles' illness to return to London, where he died in 1928 and Margaret five years later.