He attended Central High in St Paul from 1921–24, during which he published short compositions in the school newspaper and avidly read the magazine Science and Invention. In 1923 he began work part-time as a "page-boy" in the Circulation Room of the Saint Paul Public Library, filling reader's requests for books from the storage stacks; this expanded his access to, and reading of, a wide variety of literature. In 1923 and 1924 he also worked evenings at the Hill Reference Library. He attended the University of Minnesota. While there, he was a student editor and regular columnist on the student newspaper The Minnesota Daily and was also associated with the Minnesota Quarterly Magazine, as well as contributing pieces (often unsigned or pseudonymous) to the campus humour magazine Ski-U-Mah, which was edited by classmate Carl Jacobi. At that time he was enormously influenced by a reading of Arthur Machen's novel The Hill of Dreams. Wandrei graduated in 1928, with a BA in English.
At the age of 16, Wandrei completed his short story "The Red Brain", in which a mysterious Cosmic Dust sweeps through the universe, obliterating the stars. Only Antares, inhabited by a race of viscous Brains, survives – and this last remnant of universal sentience entrusts its fate to the unique, laboratory-created Red Brain in a compelling fable that leaves behind the concerns of human aquarium to revel in the cosmos and the ultimate terror waiting there.
Wandrei started writing in 1926 and his writing career took off around 1932. In late 1927 he hitchhiked from Minnesota to Rhode Island to visit H.P. Lovecraft. Lovecraft conducted him on a grand antiquarian tour of Providence and then on to similar tours in Boston, Salem and Marblehead. There was also an excursion to Warren, Rhode Island, later made famous by Wandrei's reminiscences in the Arkham House volume Marginalia (1944) during which Wandrei, Lovecraft and James Ferdinand Morton each sampled twenty-eight different flavors of ice cream at Maxfield's ice-cream parlour.
In 1925 Wandrei gave Clark Ashton Smith $50 so the Auburn poet could see Sandalwood through the press.
Wandrei's first book, begun at age 18 and published when he was but 20, was the poetry volume Ecstasy & Other Poems which was published by W. Paul Cook's The Recluse Press in 1928. The book's verse shows homage to Clark Ashton Smith and to Smith's poetic mentor George Sterling.
Wandrei's novelette "Raiders of the Universes" was the cover story in the September 1932 Astounding Stories Wandrei was active in pulp magazines until the late 1930s. He was a member of the "Lovecraft Circle", as a friend and protégé of H. P. Lovecraft, corresponding with other members of the circle (Frank Belknap Long, Clark Ashton Smith, etc.). Wandrei personally made the case for Weird Tales to publish Lovecraft's "The Call of Cthulhu" telling Farnsworth Wright that unless he published the tale, Lovecraft would look for other magazines to submit stories to.
As an accomplished poet, Wandrei was the first to write a series of sonnets for Weird Tales, "Sonnets of the Midnight Hours". Lovecraft liked the idea so much, he embarked on his own series, "Fungi From Yuggoth". Robert E. Howard also wrote his own series with "Sonnets out of Bedlam".
Wandrei's second book and second book of verse) was Dark Odyssey (Webb Publishing Co, 1931) illustrated with five illustrations by his brother Howard Wandrei.
Wandrei's only full-length fantastic novel, Dead Titans, Waken!, written in 1932, was rejected successively by three publishers – Harpers, Kendall and John Day – and finally shelved indefinitely by its author. However it was eventually destined to be published in a heavily revised version in 1948 by Arkham House as The Web of Easter Island. The original version was scheduled to be published in the late 1990s by weird fiction specialty publishing house Fedogan and Bremer but due to the dormancy of F&B, the edition was held up. It was finally published by Centipede Press in a limited edition of 300 copies in March 2012. The volume includes Wandrei's mainstream novel "Invisible Sun".
During 1933 Wandrei lived in a studio apartment in New York that was within easy walking distance of the offices of Street & Smith, who published Astounding Stories, so that Wandrei could easily bring in a new story by hand. His story "Colossus" was the first "thought variant" story (stories based on some new or not-yet-overworked idea such as other dimensions or the timetravel paradox), and helped revive the fortunes of Astounding under the editorship of his editorial mentor, F. Orlin Tremaine.
In 1939, Wandrei and August Derleth later co-founded the publishing house Arkham House to keep Lovecraft's legacy alive, an action for which Wandrei is perhaps better remembered than for his own fiction. Wandrei and Derleth co-edited the omnibus collections The Outsider and Others and Beyond the Wall of Sleep. Much of the editorial work on Lovecraft's Selected Letters series (published by Arkham House in five volumes between 1964 and 1976) was performed by Wandrei. Wandrei's interest in Arkham House centred primarily on seeing the Lovecraft writings into print; it was Derleth who brought a wider program to the press when Wandrei joined the army in 1942.
After World War II he continued writing speculative fiction stories, although at a greatly reduced rate. Some of his stories were adapted for the comic book Weird Science – "Divide and Conquer" (issue 6), based on his "A Scientist Divides" and "Monster From the Fourth Dimension" (issue 7) based on "A Monster From Nowhere".
In 1964, Arkham House published Wandrei's third book of poetry, Poems for Midnight. This volume, like his earlier Dark Odyssey, was supplemented with four pen-and-ink illustrations by his brother Howard Wandrei. The complete sonnet sequence "Sonnets of the Midnight Hours" is included, along with many other poems dating back as far as 1926 and including several reprints from both his earlier volumes of verse. Some of the early poems were revised radically for their appearance in Poems for Midnight
In 1965, Arkham House published Wandrei's second collection of short stories, Strange Harvest, which gathered 17 tales published in Weird Tales, Astounding Stories and Fantasy Magazine. The jacket drawing was by the author's brother Howard Wandrei, who had died in 1956.
In 1967, a new tale, "The Crater", appeared in the Arkham House anthology Travellers by Night.
Wandrei occupied his time editing Lovecraft's Selected Letters, whose first two volumes appeared successively in 1965 and 1968. Volume Three followed in 1971, and Volumes 4 and 5 eventually reached print in 1976.
In the 1970s Wandrei commenced a long and tedious process of litigation against Arkham House, the publishing company he had helped to found. After August Derleth's death in 1971, Donald Wandrei briefly acted as editorial director, but declined to resume his interest in the firm permanently.
1971 saw a new original tale from Wandrei, "Requiem for Mankind", which appeared in the Arkham House anthology Dark Things.
Though Wandrei had, for reasons unknown, abandoned the writing of poetry around 1934, he wrote four poems in 1977 and 1978 which he circulated amongst friends and colleagues as limited state broadsides.
Wandrei circulated iconoclastic letter-essays that denounced many of the organized forces behind the modern fantasy movement – a movement he, as a founder of Arkham House, was instrumental in setting motion.
In 1984, Wandrei was awarded the World Fantasy Award for Life Achievement. However, he refused to accept the award on the basis that the bust representing the award was a demeaning caricature of Lovecraft, whom he had known personally.
He died in St. Paul in 1987.
In 1976 Philip Rahman had met Wandrei at a convention and the two became friends. Three years after Wandrei's death in 1987, Rahman and his mostly silent partner Dennis Weiler founded the publishing firm of Fedogan and Bremer to issue work by Donald and Howard Wandrei as well as other classic pulp writers.