O'Brien was born in the borough of Brooklyn, in the state of New York. He went to Williams College and then to the University of Rochester, where he earned his bachelor's degree. He worked for Newsweek, National Geographic, and other publications as a writer and editor. With his wife and four children, he lived in New York City and subsequently Washington, DC. After his death in 1973, his wife and daughter finished Z for Zachariah with the help of his notes, which is now a blockbuster cinematic feature starring Margot Robbie, Chris Pine, and Chiwetel Ejiofor.

In addition, he is the author of Mrs. The Silver Crown and Frisby and the Rats of NIMH