Willard Huntington Wright was born to Archibald Davenport Wright and Annie Van Vranken Wright on October 15, 1888, in Charlottesville, Virginia. He attended St. Vincent College, Pomona College and Harvard University without graduating. In 1907, Wright married Katharine Belle Boynton of Seattle, Washington. He married for a second time in October 1930. His wife was Eleanor Rulapaugh, known professionally as Claire De Lisle, a portrait painter.

Wright studied art in Munich and Paris, an apprenticeship that led to a job as literary and art critic for the Los Angeles Times. Wright's early career in literature (1910 - 1919) followed literary naturalism. He wrote a novel, The Man of Promise, and some short stories in this mode. He also published similar fiction by others as editor of the New York literary magazine The Smart Set, from 1912 to 1914.

Wright's book What Nietzsche Taught appeared in 1915. It described and commented on all of Nietzsche's books, and also provided quotations from each book.

In 1917, Wright published Misinforming a Nation, in which he mounted a scathing attack on alleged inaccuracies and English biases in the Encyclopedia Britannica Eleventh Edition.

Wright continued writing as a critic and journalist until 1923, when he became ill from what was given out as overwork, but was in reality a secret drug addiction, according to John Loughery's biography Alias S.S. Van Dine. His doctor confined him to bed (supposedly because of a heart ailment, but actually because of a cocaine addiction) for more than two years. In frustration and boredom, he began collecting and studying thousands of volumes of crime and detection. In 1926 this paid off with the publication of his first S. S. Van Dine novel, The Benson Murder Case. Wright took his pseudonym from the abbreviation of "steamship" and from Van Dine, which he claimed was an old family name. According to Loughery, however, "there are no Van Dines evident in the family tree" (p. 176). He went on to write 11 more mysteries, and the first few books about his upper-class amateur sleuth, Philo Vance (who shared with Wright a love of aesthetics), were so popular that Wright became wealthy for the first time in his life, but according to critic Julian Symons:

...the pleasure was not unalloyed. His fate is curiously foreshadowed in that of Stanford West, the hero of his only novel, who sells out by abandoning the unpopular work in which he searched for "a sound foundation of culture and aristocracy" and becoming a successful novelist. The title of an article he wrote at the height of his fame, "I used to be a Highbrow and Look at Me Now", reflects both his pleasure, and his regret that he was no longer regarded seriously as a writer.

His later books declined in popularity as the reading public's tastes in mystery fiction changed. The Detectionary asserts, "Wright, who was much like Vance ... was a poseur and a dilettante, dabbling in art, music and criticism. He lived in an expensive penthouse, was fond of costly clothes and food, and collected art."

In addition to his success as a fiction writer, Wright's lengthy introduction and notes to the anthology The World's Great Detective Stories (1928) are important in the history of the critical study of detective fiction. Although dated by the passage of time, this essay is still a core around which many others have been constructed. He also wrote an article "Twenty rules for writing detective stories" in 1928 for The American Magazine. It has been reprinted a number of times, and compares to Knox's Commandments, by Ronald Knox.

Wright wrote a series of short stories for Warner Brothers film studio in the early 1930s. These stories were used as the basis for a series of 12 short films, each around 20 minutes long, that were released in 1930 - 1931. Of these, "The Skull Murder Mystery" (1931) shows Wright's vigorous plot construction. It is also notable for its non-racist treatment of Chinese characters, something quite unusual in its day. As far as it is known, none of Van Dine's screen treatments have been published in book form and none of the manuscripts survive. Short films were popular then and Hollywood made hundreds of them during the studio era. Except for a handful of comedy silents, however, most of these films are forgotten and not listed in film reference books.

Wright died April 11, 1939, in New York City, a year after the publication of an unpopular experimental novel that incorporated one of the biggest stars in radio comedy, The Gracie Allen Murder Case, and leaving a complete novelette-length story that was intended as a film vehicle for Sonja Henie, and was published posthumously as The Winter Murder Case.