Donald grew up in his parents' house at 1152 Portland Ave, St Paul and lived there most of his life save for a stint in the Army and occasional sojourns in New York and Hollywood.

Donald loved frequent rambles in the woods along the Minnesota River; it was Wandrei who later taught August Derleth the fine art of morel hunting.

Wandrei 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.

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.

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.

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.

[2] Wandrei wrote some outlines for Gang Busters and other comic books in the 1940s, and also attempted writing song lyrics in Hollywood.

After World War II, he continued writing speculative fiction stories, although at a greatly reduced rate.

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.

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.

Wandrei came in frequent contact during the 1970s with novelist and poet Richard L. Tierney, a Twin Cities resident for nine years in the 1970s.

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.