Wescott was born on a farm in Kewaskum, Wisconsin in 1901. His younger brother, Lloyd Wescott, was born in Wisconsin in 1907. He studied at the University of Chicago, where he was a member of a literary circle including Elizabeth Madox Roberts, Yvor Winters, and Janet Lewis. Independently wealthy, he began his writing career as a poet, but is best known for his short stories and novels, notably The Grandmothers (1927). He lived in Germany (1921—22), and in France (c.1925—33), where he mixed with Gertrude Stein and other members of the American expatriate community;Wescott was the model for the character Robert Prentiss in Hemingway's The Sun Also Rises.

Wescott and Wheeler returned to the United States and maintained an apartment in Manhattan with photographer George Platt Lynes. When his brother Lloyd moved to a dairy farm in Union Township near Clinton in Hunterdon County, New Jersey in 1936, Wescott along with Wheeler and Lynes took over one of the farmhand houses and called it Stone-Blossom.

His novel, The Pilgrim Hawk: A Love Story (1940), was praised by the critics. Apartment in Athens (1945), the story of a Greek couple in Nazi-occupied Athens who must share their living quarters with a German officer, was a popular success. From then on he ceased to write fiction, although he published essays and edited the works of others. In her essay on The Pilgrim Hawk Ingrid Norton writes, "After...Apartment in Athens, Wescott lived until 1987 without writing another novel: journals (published posthumously as Continual Lessons) and the occasional article, yes, but no more fiction. The Midwest-born author seems to slide into the golden handcuffs of expatriate decadence: supported by the heiress his brother married, surrounded by literate friends, given to social drinking and letter-writing."

In 1959, when his brother Lloyd acquired a farm near the village of Rosemont in Delaware Township, Hunterdon County, New Jersey, Wescott moved into a two-story stone house on the property, dubbed Haymeadows. In 1987 Wescott died of a stroke at his home in Rosemont.