Miller was born in 1894 in Hanford, California. Growing up the granddaughter of early California pioneers, Miller was privy to many stories of the earliest California settlers. Consequently Miller gained an intimate understanding of the early southern San Joaquin landscape and the domestic life of those pioneers who settled there. Miller attended the University of California and the University of Minnesota and participated in the prestigious Bread Loaf Writers' Conference hosted by Middlebury College. At this conference, Miller studied with western historian and novelist Bernard DeVoto and subsequently converted the various stories she heard growing up into a unified novel. Miller published the resulting novel, First the Blade, in 1938. The novel depicts the daily life of Californian pioneers through the perspective of a fictional woman settler. The novel also includes a fictionalized account of the Mussel Slough gunfight that resulted from a land dispute between local pioneer settlers and the Southern Pacific Railroad. The novel is praised for its unique female perspective on pioneer life as well as for its verisimilitude and detailed realism. In 1949, Miller published a book of poetry entitled Mother Lode, 1849 to 1949.
Today UCLA annually awards the May Merrill Miller award to a female student for work in fiction or poetry.