Updike was born in Reading, Pennsylvania, the only child of Linda Grace (née Hoyer) and Wesley Russell Updike, and was raised at his childhood home in the nearby small town of Shillington. The family later moved to the unincorporated village of Plowville. His mother's attempts to become a published writer impressed the young Updike. "One of my earliest memories", he later recalled, "is of seeing her at her desk ... I admired the writer's equipment, the typewriter eraser, the boxes of clean paper. And I remember the brown envelopes that stories would go off in—and come back in."

These early years in Berks County, Pennsylvania, would influence the environment of the Rabbit Angstrom tetralogy, as well as many of his early novels and short stories. Updike graduated from Shillington High School as co-valedictorian and class president in 1950 and received a full scholarship to Harvard College, where he was the roommate of Christopher Lasch during their first year. Updike had already received recognition for his writing as a teenager by winning a Scholastic Art & Writing Award, and at Harvard he soon became well known among his classmates as a talented and prolific contributor to The Harvard Lampoon, of which he was president. He studied with dramatist Robert Chapman, the director of Harvard's Loeb Drama Center. He graduated summa cum laude in 1954 with a degree in English and was elected to Phi Beta Kappa.

Biographer Adam Begley wrote that Updike "transmuted the minutiae of his life" in prose, which enriched his readers at the cost of being "willing to sacrifice the happiness of people around him for his art".

In 1953, while a student at Harvard, Updike married Mary Entwistle Pennington, an art student at Radcliffe College and daughter of a prominent Unitarian minister. She accompanied him to Oxford, England, where she attended art school and their first child, Elizabeth, was born in 1955. The couple had three more children together: David (born 1957), Michael (born 1959), and Miranda (born 1960).

Updike was serially unfaithful, and eventually left the marriage in 1974 for Martha Ruggles Bernhard. In 1977, Updike and Bernhard married. In 1982, his first wife married an MIT academic. Updike and Bernhard lived for more than 30 years in Beverly Farms, Massachusetts. Updike had three stepsons through Bernhard. He died of lung cancer at a hospice in Danvers, Massachusetts, on January 27, 2009, at age 76. He was survived by seven grandchildren and seven step-grandchildren.

Updike published eight volumes of poetry over his career, including his first book The Carpentered Hen (1958), and one of his last, the posthumous Endpoint (2009). The New Yorker published excerpts of Endpoint in its March 16, 2009 issue. Much of Updike's poetical output was recollected in Knopf's Collected Poems (1993). He wrote that "I began as a writer of light verse, and have tried to carry over into my serious or lyric verse something of the strictness and liveliness of the lesser form." The poet Thomas M. Disch noted that because Updike was such a well-known novelist, his poetry "could be mistaken as a hobby or a foible"; Disch saw Updike's light verse instead as a poetry of "epigrammatical lucidity". His poetry has been praised for its engagement with "a variety of forms and topics", its "wit and precision", and for its depiction of topics familiar to American readers.

British poet Gavin Ewart praised Updike for the metaphysical quality of his poetry and for his ability "to make the ordinary seem strange", and called him one of the few modern novelists capable of writing good poetry. Reading Endpoint aloud, the critic Charles McGrath claimed that he found "another, deeper music" in Updike's poetry, finding that Updike's wordplay "smooths and elides itself" and has many subtle "sound effects". John Keenan, who praised the collection Endpoint as "beautiful and poignant", noted that his poetry's engagement with "the everyday world in a technically accomplished manner seems to count against him".