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 left the family 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.

Moore came to the attention of poets as diverse as Wallace Stevens, William Carlos Williams, H.D., T. S. Eliot, and Ezra Pound beginning with her first publication in 1915. 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; much later, she encouraged promising young poets, including Elizabeth Bishop, Allen Ginsberg, John Ashbery and James Merrill.

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 with Ezra Pound from 1919, even during his incarceration. She opposed Benito Mussolini and Fascism from the start and objected to Pound's antisemitism. Moore herself was a conservative Republican and supported Herbert Hoover in 1928 and 1932. She was a life-long ally and friend of the American poet Wallace Stevens. See for instance her review of Stevens's first anthology, Harmonium, and in particular her comment about the influence of Henri Rousseau on the poem "Floral Decorations for Bananas'".

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:

:::nor is it valid

:::::to discriminate against "business documents and

:school-books": all these phenomena are important. One must make a distinction

::::however: when dragged into prominence by half poets, the result is not poetry

In 1955, Moore was informally invited by David Wallace, manager of marketing research for Ford's "E-car" project, and his co-worker Bob Young to provide input with regard to the naming of the car. Wallace's rationale was "Who better to understand the nature of words than a poet?" On October 1955, Moore was approached to submit "inspirational names" for the E-car, and on November 7, she offered her list of names, which included such notables as "Resilient Bullet", "Ford Silver Sword", "Mongoose Civique", "Varsity Stroke", "Pastelogram" and "Andante con Moto." On December 8, she submitted her last and most famous name, "Utopian Turtletop." The E-car was finally christened by Ford as the Edsel.

Not long after throwing the first pitch for the 1968 season in Yankee Stadium, Moore suffered a stroke. She suffered a series of strokes thereafter, and died in 1972. She was interred in Gettysburg's Evergreen Cemetery.

Moore never married. Her living room has been preserved in its original layout in the collections of the Rosenbach Museum & Library in Philadelphia. Her entire library, knick-knacks (including a baseball signed by Mickey Mantle), all of her correspondence, photographs, and poetry drafts are available for public viewing.

Like Robert Lowell, Moore revised a great many of her early poems (including "Poetry") in later life. These appeared in The Complete Poems of 1967, after which critics tended to accept as canonical the "elderly Moore's revisions of the exuberant texts of her own poetic youth." Facsimile editions of the theretofore out-of-print 1924 Observations became available in 2002. Since that time there has been no critical consensus about which versions are authoritative.

In 1996, she was inducted into the St. Louis Walk of Fame.