Roethke was born in Saginaw, Michigan. His father, Otto, was a German immigrant, a market-gardener who owned a large local greenhouse, along with his brother (Theodore's uncle). Much of Theodore's childhood was spent in this greenhouse, as reflected by the use of natural images in his poetry. The poet's adolescent years were jarred, however, by his uncle's suicide and by the death of his father from cancer, both in early 1923, when Theodore (Ted) was only 15. These deaths shaped Roethke's psyche and creative life.

He attended the University of Michigan, then he briefly attended law school before entering Harvard University, where he studied under the poet Robert Hillyer. Abandoning graduate study because of the Great Depression, he taught English at several universities, including Lafayette College, Pennsylvania State University, and Bennington College.

In 1940, he was expelled from his position at Lafayette and he returned to Michigan. Just prior to his return, he had an affair with established poet and critic Louise Bogan, who later became one of his strongest early supporters. While teaching at Michigan State University in East Lansing, he began to suffer from manic depression, which fueled his poetic impetus. His last teaching position was at the University of Washington, leading to an association with the poets of the American Northwest.

In 1953, Roethke married Beatrice O'Connell, a former student. Like many other American poets of his generation, Roethke was a heavy drinker and susceptible, as mentioned, to bouts of mental illness. He did not inform O'Connell of his repeated episodes of depression, yet she remained dedicated to him and his work. She ensured the posthumous publication of his final volume of poetry, The Far Field, which includes the poem "Meditation at Oyster River."

In 1961, "The Return" was featured on George Abbe's album Anthology of Contemporary American Poetry on Folkways Records. The following year, Roethke released his own album on the label entitled, Words for the Wind: Poems of Theodore Roethke.

He suffered a heart attack in his friend S. Rasnics' swimming pool in 1963 and died on Bainbridge Island, Washington, aged 55. The pool was later filled in and is now a zen rock garden, which can be viewed by the public at the Bloedel Reserve, a 150-acre (60 hectare) former private estate. There is no sign to indicate that the rock garden was the site of Roethke's death.

There is a sign that commemorates his boyhood home and burial in Saginaw, Michigan. The historical marker notes in part:

Theodore Roethke (1908–1963) wrote of his poetry: The greenhouse "is my symbol for the whole of life, a womb, a heaven-on-earth." Roethke drew inspiration from his childhood experiences of working in his family's Saginaw floral company. Beginning is 1941 with Open House, the distinguished poet and teacher published extensively, receiving a Pulitzer Prize for poetry and two National Book Awards among an array of honors. In 1959 Pennsylvania University awarded him the Bollingen Prize. Roethke taught at Michigan State College, (present-day Michigan State University) and at colleges in Pennsylvania and Vermont, before joining the faculty of the University of Washington at Seattle in 1947. Roethke died in Washington in 1963. His remains are interred in Saginaw's Oakwood Cemetery.

The Friends of Theodore Roethke Foundation maintains his birthplace at 1805 Gratiot in Saginaw as a museum.

In Against Oblivion, an examination of forty-five twentieth century poets, the critic Ian Hamilton wrote: "Roethke's best gift as a poet was for touching, small-scale lyricism (see Elegy for Jane, My Papa's Waltz). More and more though he was drawn towards what he believed to be the 'major' themes: man and God, Eternity, the Universe, and so on. Spiritual afflatus took over from direct experience; inspiration was supplanted by ambition. In this sense, Roethke was a typical mid-century case study." "Early on, the chief influence was W.H.Auden. Later, Roethke turned to Walt Whitman - who ... seems to have directed Roethke back to the intent scrutiny of nature that marked his early, so-called 'greenhouse' poems. In Roethke's second book, The Lost Son, there are several of these greenhouse poems and they are among the best things he wrote; convincing and exact, and rich in loamy detail."

Critical opinion of his later poems is mixed, with some critics pointing toward The Far Field as a resounding final accomplishment and others as an incomplete book of mixed quality. The book itself is filled with polarity, dealing with the twin strains of physical and spiritual reality within Roethke's mysticism (which matured during his final years), chiefly dealt with in the "North American Sequence" and "Sequence, Sometimes Metaphysical".