Moore was born in Kirkwood, Missouri, in the manse of the Presbyterian church where her maternal grandfather, John Riddle Warner, served as pastor. She was the daughter of construction engineer and inventor John Milton Moore and his wife, Mary Warner. She grew up in her grandfather's household; her father having been committed to a mental hospital before her birth. In 1905, Moore entered Bryn Mawr College in Pennsylvania and graduated four years later. She taught at the Carlisle Indian Industrial School in Carlisle, Pennsylvania, until 1915, when Moore began to publish poetry professionally.

In part because of her extensive European travels before the First World War, Moore came to the attention of poets as diverse as Wallace Stevens, William Carlos Williams, H.D., T. S. Eliot, and Ezra Pound. From 1925 until 1929, Moore served as editor of the literary and cultural journal The Dial. This continued her role, similar to that of Pound, as a patron of poetry, encouraging promising young poets, including Elizabeth Bishop, Allen Ginsberg, John Ashbery and James Merrill, and publishing early work, as well as refining poetic technique.

In 1933, Moore was awarded the Helen Haire Levinson Prize from Poetry. Her Collected Poems of 1951 is perhaps her most rewarded work; it earned the poet the Pulitzer Prize, the National Book Award, and the Bollingen Prize. Moore became a minor celebrity, in New York literary circles, serving as unofficial hostess for the Mayor. She attended boxing matches, baseball games and other public events, dressed in what became her signature garb, a tricorn hat and a black cape. She particularly liked athletics and athletes, and was a great admirer of Muhammad Ali, for whose spoken-word album, I Am the Greatest!, she wrote liner notes. Moore continued to publish poems in various journals, including The Nation, The New Republic, and Partisan Review, as well as publishing various books and collections of her poetry and criticism. Moore corresponded for a time with W. H. Auden and Ezra Pound during the latter's incarceration.

Her most famous poem is perhaps the one entitled, appropriately, "Poetry", in which she hopes for poets who can produce "imaginary gardens with real toads in them." It also expressed her idea that meter, or anything else that claims the exclusive title, "poetry," is not as important as delight in language and precise, heartfelt expression in any form. She often composed her own poetry in syllabics. These syllabic lines from "Poetry" illustrate her position: poetry is a matter of skill and honesty in any form whatsoever, while anything written poorly, although in perfect form, cannot be poetry:

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