Roethke was born in Saginaw, Michigan and grew up on the west side of the Saginaw River. His father, Otto, was a German immigrant, a market-gardener who owned a large local 25-acre 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. In early 1923 when Roethke was 15 years old, his uncle committed suicide and his father died of cancer. Roethke noted that these events affected him deeply and influenced his work.
Roethke attended the University of Michigan, earning a B.A. magna cum laude and Phi Beta Kappa. He continued on at Michigan to receive a M.A. in English. He briefly attended the University of Michigan School of Law before entering graduate school at 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 Michigan State University, Lafayette College, Pennsylvania State University, and Bennington College.
In 1940, he was expelled from his position at Lafayette and he returned to Michigan. Prior to his return, he had an affair with established poet and critic Louise Bogan, 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.
Some of his best known students included James Wright, Carolyn Kizer, Tess Gallagher, Jack Gilbert, Richard Hugo, and David Wagoner. The highly introspective nature of Roethke's work greatly influenced the poet Sylvia Plath. So influential was Roethke's poetry on Plath's mature poetry that when she submitted "Poem for a Birthday" to Poetry magazine, it was turned down because it displayed "too imposing a debt to Roethke."
In 1952, Roethke received a Ford Foundation grant to "expand on his knowledge of philosophy and theology", and spent most of his time from June 1952 to September 1953 reading primarily existential works. Among the philosophers and theologians he read were Sören Kierkegaard, Evelyn Underhill, Meister Eckhart, Paul Tillich, Jacob Boehme, and Martin Buber.
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 to bouts of mental illness. He did not initially inform O'Connell of his repeated episodes of mania and depression, yet she remained dedicated to him and his work. She ensured the posthumous publication of his final volume of poetry, The Far Field, as well as a book of his collected children's verse, Dirty Dinky and Other Creatures, in 1973. From 1955 to 1956 he spent one year in Italy on a scholarship of the U.S.-Italy Fulbright Commission.
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 in 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.
Roethke Auditorium (Kane Hall 130) at the University of Washington is named in his honor.
In 1995, the Seattle alley between Seventh and Eighth Avenues N.E. running from N.E. 45th Street to N.E. 47th Street was named Roethke Mews in his honor. It adjoins the Blue Moon Tavern, one of Roethke's haunts.
In 2016, the Theodore Roethke Home museum announce their "quest to find as many as possible of the 1,000 hand-numbered copies of [...] Roethke's debut collection, Open House, to celebrate the 75th anniversary of the work's publication."