Woolrich was born of English, Spanish and Jewish descent. His father, a civil engineer, separated from his mother when he was young. He lived for a time in Mexico with his father before returning to New York City to live with his mother, Claire Attalie Woolrich.

He attended Columbia University but left in 1926 without graduating when his first novel, Cover Charge, was published. Cover Charge was a Jazz Age work inspired by the work of F. Scott Fitzgerald. He soon turned to pulp and detective fiction, often published under his pseudonyms. For example, William Irish was the byline in Dime Detective Magazine (February, 1942) on his 1942 story "It Had to Be Murder," (source of the 1954 Alfred Hitchcock movie Rear Window) and based on H. G. Wells' short story Through A Window. François Truffaut filmed Woolrich's The Bride Wore Black and Waltz Into Darkness in 1968 and 1969, respectively, the latter as Mississippi Mermaid. Ownership of the copyright in Woolrich's original story "It Had to Be Murder" and its use for Rear Window was litigated before the United States Supreme Court in Stewart v. Abend, 495 U.S. 207 (1990).

Woolrich was homosexual, and quite promiscuous in his youth. In 1930, whilst working as a screenwriter in Los Angeles, Woolrich married Violet Virginia Blackton (1910-65), daughter of silent film producer J. Stuart Blackton. They separated after three months, and the marriage was annulled in 1933.

Woolrich returned to New York where he and his mother moved into the Hotel Marseilles (Broadway and West 102nd Street). He lived there until her death on October 6, 1957, which prompted his move to the Hotel Franconia (20 West 72nd Street).

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 of about $850,000 to Columbia University, to endow scholarships in his mother's memory for journalism students.

Woolrich's novels written between 1940 to 1948 are considered his principal legacy. During this time, he definitively became an author of novel-length crime fiction which stand apart from his first six works, written under the influence of F. Scott Fitzgerald.

Most of Woolrich's books are out of print, and new editions have not come out because of estate issues. However, new collections of his short stories were issued in the early 1990s.

Woolrich died leaving fragments of an unfinished novel, The Loser; fragments have been published separately and also collected in Tonight, Somewhere in New York (2005).

• Cover Charge (1926)
• Children of the Ritz (1927)
• Times Square (1929)
• A Young Man's Heart (1930)
• The Time of Her Life (1931)
• Manhattan Love Song (1932)
• The Bride Wore Black (1940)
• The Black Curtain (1941)
• Marihuana (1941, as William Irish)
• Black Alibi (1942)
• Phantom Lady (1942, as William Irish)
• The Black Angel (1943, based on his 1935 story Murder in Wax)
• The Black Path of Fear (1944)
• After Dinner Story (1944, as William Irish)
• Deadline at Dawn (1944, as William Irish)
• Night Has a Thousand Eyes (1945, as George Hopley)
• Waltz into Darkness (1947, as William Irish)
• Rendezvous in Black (1948)

• I Married a Dead Man (1948, as William Irish)
• Savage Bride (1950)
• Fright (1950, as George Hopley)
• You'll Never See Me Again (1951)
• Strangler's Serenade (1951, as William Irish)
• Hotel Room (1958)
• Death is My Dancing Partner (1959)
• The Doom Stone (1960, previously serialized in Argosy 1939)
• Into the Night (1987, an unfinished manuscript finished by Lawrence Block)