Sexton suffered from severe mental illness for much of her life, her first manic episode taking place in 1954. After a second episode in 1955 she met Dr. Martin Orne, who became her long-term therapist at the Glenside Hospital. It was Dr. Orne who encouraged her to take up poetry.
The first poetry workshop she attended was led by John Holmes. Sexton felt great trepidation about registering for the class, asking a friend to make the phone call and accompany her to the first session. She found early acclaim with her poetry; a number were accepted by The New Yorker, Harper's Magazine and the Saturday Review. Sexton later studied with Robert Lowell at Boston University alongside distinguished poets Sylvia Plath and George Starbuck.
Sexton's poetic career was encouraged by her mentor W.D. Snodgrass, whom she met at the Antioch Writer's Conference in 1957. His poem "Heart's Needle" proved inspirational for her in its theme of separation from his three-year-old daughter. Sexton first read the poem at a time when her own young daughter was living with her mother-in-law. She, in turn, wrote "The Double Image", a poem which explores the multi-generational relationship between mother and daughter. Sexton began writing letters to Snodgrass and they became friends.
While working with John Holmes, Sexton encountered Maxine Kumin. They became good friends and remained so for the rest of Sexton's life. Kumin and Sexton rigorously critiqued each other's work and wrote four children's books together. In the late 1960s, the manic elements of Sexton's illness began to affect her career, though she still wrote and published work and gave readings of her poetry. She collaborated with musicians, forming a jazz-rock group called "Her Kind" that added music to her poetry. Her play Mercy Street, starring Marian Seldes, was produced in 1969, after several years of revisions. Sexton also collaborated with the artist Barbara Swan, who illustrated several of her books.
Within twelve years of writing her first sonnet, she was one of the most honored poets in America: a Pulitzer Prize winner, a fellow of the Royal Society of Literature and the first female member of the Harvard chapter of Phi Beta Kappa.