Reznikoff was born in a Jewish neighborhood in Brooklyn, New York of Russian parents. After a year studying journalism, he entered the law school of New York University in 1912 and graduated in 1916. He practiced law briefly and entered officer training school in 1918, but failed to see active service before the end of the war.

Reznikoff worked for a time for his family's business as a hat salesman. He then worked for a legal publishing house where he wrote summaries of court records for legal reference books. This experience was to prove important for his later writing.

From his teens, Reznikoff had been writing poetry, much of it influenced by the Imagists, and publishing it using a second-hand press, for which he set the type himself. Throughout his writing life, Reznikoff was always concerned to ensure that his work was published, even at his own expense. This appears to have been inspired by a family story of his grandfather, an unpublished Hebrew poet whose manuscripts were destroyed after his death.

Around the time the Objectivist issue of Poetry appeared, Reznikoff, Zukofsky and George Oppen set up To Publishers and later the Objectivist Press, essentially to publish their own work. Reznikoff had had some success with his 1930 novel By the Waters of Manhattan, and the new press published three titles by him, two that gathered together previously self-published work and the third a first installment of a long work called Testimony.

Testimony was, initially, a prose retelling of stories that Reznikoff had discovered while working on court records. In these stories, Reznikoff discovered something of the story of America between 1855 and 1915 both in its diversity and its violence. Tellingly, he chose to omit the judgements, focusing on the stories themselves.

Over the following forty years, Reznikoff worked on turning these stories into an extended found poem that finally ran to some 500 pages over two volumes. He aimed to present the stories in as near as possible the words of the participants, and the result was a poetry almost entirely stripped of metaphor and of authorial personality and emotion. In this sense, Testimony can be read as the great monument of Objectivist poetry.

The poetic mode developed in the making of this work was to prove invaluable when Reznikoff started work on Holocaust, which was based on courtroom accounts of Nazi concentration camps. He also adopted this style for many of his poetic retellings of stories from the Old Testament.

Reznikoff lived and wrote in relative obscurity for most of his life, with his work being either self-published or issued by small independent presses. In the early 1960s, this situation seemed set to change when New Directions Publishers, at the behest of friend and fellow poet George Oppen, together with Oppen's sister June Oppen Degnan's press San Francisco Review Books published two books, including the first installment of the verse Testimony. However, critical reaction to this book was generally negative and Reznikoff once again found himself publishing his own work.

In 1971, he was awarded the Morton Dauwen Zabel Prize of $2,500 by The National Institute of Arts and Letters. He also found a new publisher around this time, Black Sparrow Press. They published By the Well of Living and Seeing: New and Selected Poems, 1918-1973 in 1974. At the time of his death, Reznikoff was correcting proofs of the first volume of the Black Sparrow Collected Poems. In the years immediately following his death, Black Sparrow brought all his major poetry and prose works back into print.