She was born Theodora Brenton Eliot McCormick in Brooklyn in 1890 to Eliot McCormick and Laura Case Brenton McCormick. Du Bois' father died when she was a year old. Laura remarried in 1897 and her second husband, Charles MacDonald (1857-1945), was a lawyer and Wall Street broker. He had a son, Sam (1886-1965), from a previous marriage, and together the couple had one child that survived infancy, Howard (1898-1965). Although Du Bois continued to visit her father's relatives, her stepfather and mother were not on good terms with them. A poor relationship with her stepfather is reflected in Du Bois' writing.
From 1897-1900, the family lived in Manhattan and Du Bois attended the Barnard School for Girls. After moving to Yonkers in 1900, Du Bois attended the Halsted School and received a classical education. She was diagnosed with tuberculosis at 21 and spent several months in a sanatorium. She wrote poetry and plays, including children's plays, and attended the Dartmouth Summer School for Drama in 1916. She co-authored Amateur and Educational Dramatics (1917) with Evelyne Hilliard and Kate Oglebay.
Theodora met Delafield Du Bois in Connecticut in 1917, and they were married the following year. Delafield Du Bois was ten years older than Theodora. He was an electrical engineer but also pursued other research interests. The Du Bois's moved to Dongan Hills on Staten Island. The couple had two children, Theodora in 1919 and Eliot in 1922. Du Bois continued writing short stories and plays. Her first published short story, "Thursday and the King and Queen," was published in Women's Home Companion in 1920 and she continued to publish short stories throughout the 1920's. In 1928, Delafield Du Bois left his job to pursue research and the family went to Europe for 18 months, spending time in Munich, Cambridge, Italy and Ireland. The experiences from this travel informed many of Du Bois' future works.
Du Bois went on to try writing novels and the first, The Devil's Spoon, was published in 1930. The family moved to Connecticut during this period, and Du Bois wrote plays. In 1934, the family moved to New Haven where they lived until Delafield Du Bois' retirement after the end of World War II (1946). Du Bois now began detective writing in earnest. Twenty of her detective stories were published during 1941-1954, and many were translated and published abroad.
On Delafield's retirement the Du Bois's bought a boat, and spent nine months of each of the three successive years sailing. A number of Du Bois' novels are based upon her sailing experiences including Rogue's Coat (1949). The family returned to Dongan Hills on Staten Island but later spent time in Ireland.
Du Bois began to experience professional difficulties during the 1950's. She changed agents early in 1952, leaving Paul R. Reynolds, who had been her agent since the 1910's, and going to McIntosh & Otis. This was partially because a cousin by marriage, Mary Abbot, was a partner in McIntosh & Otis, but also because the Reynolds agency encouraged her to write a historical novel on Ireland, Where the Blackthorn Grows, which was rejected by publishers. There were also problems associated with the publication of Seeing Red (1954). Seeing Red was part of the series of McNeill mystery stories that had begun with Armed with a New Terror (1936). The book was a sequel to Murder Strikes an Atomic Unit (1946), which dealt with the theft of atomic secrets. The plot of Seeing Red involves the appearance of the McNeills as suspects before the House Un-American Activities Committee. Du Bois had been appalled when she had gone to Washington to research and observe the committee and portrayed it negatively in the book. The caused backlash against her and the book's publisher, Doubleday, received angry letters on the issue, although Du Bois was not informed of them at the time due to health problems. Doubleday did not publish any additional McNeill mysteries after this incident, although they had previously published several of Du Bois' books as part of their Crime Club.
Except for Freedom's Way (1953), which made the New York Times Best Seller list, Du Bois's later novels were not particularly successful. Despite these personal and professional setbacks, Du Bois continued writing and the CUNY collection contains several unpublished manuscripts written in her later years.