The son of Quaker parents, Brown was of delicate constitution, and he early devoted himself to study. He was apprenticed to a Philadelphia lawyer in 1787, but he had a strong interest in writing that led him to help found a literary society. In 1793 he gave up the law entirely to pursue a literary career in Philadelphia and New York City.

His first novel, Wieland (1798), a minor masterpiece in American fiction, shows the ease with which mental balance is lost when the test of common sense is not applied to strange experiences. The story concerns Theodore Wieland, whose father died by spontaneous combustion apparently for violating a vow to God. The younger Wieland, also a religious enthusiast seeking direct communication with divinity, misguidedly assumes that a ventriloquist's utterances are supernatural in origin; driven insane, he acts upon the prompting of this “inner voice” and murders his wife and children. When apprised of his error, he kills himself. Brown also wrote Ormond (1799), Edgar Huntly (1799), and Arthur Mervyn (1799–1800), as well as a number of less well known novels and a book on the rights of women. Despite this literary output, Brown engaged in trade throughout his life to support his family.