Lowell was born in Boston, Massachusetts to a Boston Brahmin family that included poets Amy Lowell and James Russell Lowell. His mother, Charlotte Winslow, was a descendant of William Samuel Johnson, a signer of the United States Constitution, with Jonathan Edwards, the famed Calvinist theologian, Anne Hutchinson, the Puritan preacher and healer, Robert Livingston the Elder, Thomas Dudley, the second governor of Massachusetts, and Mayflower passengers James Chilton and his daughter Mary Chilton. He was went to St. Mark's School, a prominent prep-school in Southborough, Massachusetts, before attending Harvard College for two years and transferring to Kenyon College in Gambier, Ohio, to study under John Crowe Ransom.

He converted from Episcopalianism to Catholicism, which influenced his first two books, Land of Unlikeness (1944) and the Pulitzer Prize—winning Lord Weary's Castle (1946). By the end of the forties, he left the Catholic Church. In 1950, Lowell was included in the influential anthology Mid-Century American Poets as one of the key literary figures of his generation. Among his contemporaries who also appeared in that book were Muriel Rukeyser, Karl Shapiro, Elizabeth Bishop, Theodore Roethke, Randall Jarrell, and John Ciardi, all poets who came into prominence in the 1940s. From 1947, Lowell taught for several years in the Iowa Writers' Workshop at the University of Iowa, together with Paul Engle, Robie Macauley, and Anthony Hecht .

Lowell was a conscientious objector during World War II and served several months at the federal prison in Danbury, Connecticut. He would later write about his experience in prison in the poem "Memories of West Street and Lepke" from his book Life Studies. In 1949, he was involved in Yaddo's share of the Red Scare when he attempted unsuccessfully to oust Yaddo's director Elizabeth Ames who was being questioned by the FBI for her alleged involvement with writer Agnes Smedley, who was being accused of spying for the Soviet Union. During the 1960s he was active in the civil rights movement and opposed the US involvement in Vietnam. His participation in the October 1967 peace march in Washington, DC and his subsequent arrest are described in the early sections of Norman Mailer's The Armies of the Night.

He was married to novelist Jean Stafford from 1940 - 1948. Then in 1949 he married the writer Elizabeth Hardwick with whom he had a daughter, Harriet, in 1957. In 1970 he left Elizabeth Hardwick for the British author Lady Caroline Blackwood and spent many of his last years with Blackwood in England. He suffered from alcoholism and manic depression and was hospitalized many times throughout his life. He died in 1977, having suffered a heart attack in a cab in New York City on his way to see Hardwick. He is buried in Stark Cemetery, Dunbarton, New Hampshire.

He reached wide acclaim for his 1946 book, Lord Weary's Castle, which included ten poems slightly revised from his earlier Land of Unlikeness, and thirty new poems. Among the better known poems in the volume are "Mr Edwards and the Spider" and "The Quaker Graveyard in Nantucket." Lord Weary's Castle was awarded the Pulitzer Prize in 1947. Lowell's early poems are formal, ornate, and concerned with violence and theology; a typical example is the close of "The Quaker Graveyard" -- "You could cut the brackish winds with a knife / Here in Nantucket and cast up the time / When the Lord God formed man from the sea's slime / And breathed into his face the breath of life, / And the blue-lung'd combers lumbered to the kill. / The Lord survives the rainbow of His will." He was Consultant in Poetry to the Library of Congress for 1947?1948 (a position now known as the U.S. Poet Laureate).

The Mills of the Kavanaughs (1951), a book that centered on its epic title poem, did not receive similar acclaim, but Lowell was able to revive his reputation with Life Studies (1959). The poems in this book were written in a mix of free and metered verse, with much more informal language than he used in his first two books. It marked both a big turning point in Lowell's career, and a turning point for American poetry in general. Because many of the poems documented details from Lowell's family life and personal problems, one critic, M.L. Rosenthal, labeled the book "confessional." For better or worse, this label stuck. Lowell's editor and friend Frank Bidart notes in his afterword to Lowell's Collected Poems, "Lowell is widely, perhaps indelibly associated with the term 'confessional,'" though Bidart questions the accuracy of this label.

Lowell followed Life Studies with Imitations, a volume of loose translations of poems by classical and modern European poets, including Rilke, Montale, Baudelaire, Pasternak, and Rimbaud, for which he received the 1962 Bollingen Poetry Translation Prize. However, critical response to Imitations was mixed and sometimes hostile (as was the case with Vladimir Nabokov's public response to Lowell's Mandelstam translations). In the book's introduction, Lowell explained that his idiosyncratic translations should be thought of as "imitations" rather than strict translations since he took many liberties with the originals, trying to "do what [his] authors might have done if they were writing their poems now and in America."

His next book For the Union Dead (1964) was widely praised, particularly for its title poem, which invokes Allen Tate's "Ode to the Confederate Dead." In Near the Ocean, which followed a couple of years later, Lowell had returned to stanzaic forms, and the second half of the book marks Lowell's return to writing loose translations (including verse approximations of Dante, Juvenal, and Horace). The best known poem in this volume is "Waking Early Sunday Morning," which was written in eight-line stanzas (borrowed from Andrew Marvell's poem "Upon Appleton House") and showed politics beginning to enter Lowell's work.

During 1967 and 1968 he experimented with a verse journal, published as Notebook, 1967-68. These fourteen-line poems loosely based on the sonnet form were reworked into three volumes. History deals with public history from antiquity up to the mid-20th century (although the book doesn't always follow a linear or logical path and contains many poems about Lowell's friends, peers, and family). For Lizzie and Harriet describes the breakdown of his second marriage and contains poems that are supposed to be in the voice of his daughter, Harriet, and his second wife, Elizabeth. Finally, the last work in Lowell's sonnet sequence, The Dolphin, which won the 1974 Pulitzer Prize, includes poems about his daughter, his ex-wife, and his new wife Caroline Blackwood whom he'd affectionately nicknamed "Dolphin." A minor controversy erupted when Lowell admitted to having incorporated (and altered) private letters from his ex-wife, Elizabeth Hardwick into poems for The Dolphin. He was particularly criticized for this by his friends, fellow-poets Adrienne Rich and Elizabeth Bishop.

Lowell published his last volume of poetry, Day by Day, in 1977 (also the year of his death). The book was Lowell's only volume to contain nothing but free verse, and for fans of Lowell's work who were disappointed by the rather uneven "sonnets" that Lowell had been re-writing and re-packaging in volume after volume since 1967, Day by Day marked a return to form.

Lowell's Collected Poems, edited by Frank Bidart and David Gewanter, were published in 2003.The Letters of Robert Lowell, edited by Saskia Hamilton, was published in 2005. Both volumes received overwhelmingly positive critical responses from the mainstream press, and their publication has since led to a renewed interest in Lowell's writing.