Born April 5, 1941 in Philadelphia, Pennsylvania, William Charles Henderson attended Hamilton College and pursued graduate studies briefly at both Harvard and the University of Pennsylvania. He and his uncle Howard Galloway started the small publishing house Nautilus Books in 1970, which then published Henderson's first novel The Galapagos Kid under the pseudonym Luke Walton. Neither the novel nor the publishing house proved successful.

In 1973 Henderson launched the Pushcart Press with The Publish it Yourself Handbook-Literary Tradition and How-To Without Commercial or Vanity Publishers, compiled and edited by him. The handbook was not only successful but has seen several reprintings over the years. He started the Pushcart Prize series in 1976. This annual anthology that celebrates small presses and little magazines and their writers has continued without interruption. In 1982 Henderson started the Editors' Book Award for overlooked manuscripts. In this program he asks editors at commercial houses to nominate manuscripts they were not able to publish because of financial pressure. He then chooses one from these nominations and publishes it by Pushcart Press.

Over the years several selections published in this series have been reprinted in mass market and trade paperback editions, occasionally by the very commercial house that had rejected them the first time around. In addition to his editing and publishing work, Henderson has also written several volumes of memoirs, essays and book reviews for the New York Times, Publishers Weekly and elsewhere, and has been a visiting lecturer at several colleges and summer writing programs.