Woolrich's parents separated when he was young. He lived for a time in Mexico with his father, a civil engineer, before returning to New York City to live with his mother Claire.
He attended Columbia University, but left without graduating in 1926, upon the publication of his first novel, Cover Charge, a Jazz Age work inspired by the work of F Scott Fitzgerald. He soon turned to pulp and detective fiction, often published under the pseudonyms George Hopley and William Irish. For example, he published his 1942 story "It Had to be Murder", the basis of the 1954 Alfred Hitchcock movie Rear Window, by the pseudonym William Irish. François Truffaut filmed Woolrich's The Bride Wore Black and Waltz Into Darkness in 1968 and 1969, respectively, the latter as Mississippi Mermaid.
In his youth, Woolrich was a promiscuous homosexual. In 1930, while living in Los Angeles and working as a writer in the film industry, Woolrich married Violet Virginia Blackton (1910-1965), daughter of silent film producer J. Stuart Blackton. They separated after 3 months and the marriage was annulled in 1933. He left his ex-wife a locked suitcase containing a diary detailing his sexual adventures.
Woolrich spent the next 35 years living in the same seedy Harlem, New York residential hotel as his mother, often moving in and out of her apartment. He never allowed her to read any of his work.
Following his mother's death in 1957, Woolrich moved in and out of various hotels in New York. Alcoholism and an amputated leg (caused by an infection from a too-tight shoe which went untreated) left him a recluse, although he did socialize on occasion with young admirers such as writer Ron Goulart. He did not attend the premiere of Truffaut's film of his novel The Bride Wore Black in 1968, even though it was held in New York City. He died weighing 89 pounds. He is interred in the Ferncliff Cemetery in Hartsdale, New York.
Woolrich bequeathed his estate to Columbia University, to endow scholarships in his mother's memory for journalism students. Woolrich died leaving fragments of an unfinished novel called The Loser. Most fragments have been published separately, but were recently collected in Tonight, Somewhere in New York.
Cornell Woolrich's biographer, Francis Nevins Jr., rated Woolrich the fourth best crime writer of his day, behind only Dashiell Hammett, Erle Stanley Gardner and Raymond Chandler. Some of his best known works were published under the pseudonyms William Irish and George Hopley.