Sale graduated from Cornell University, majoring in history, in 1958. He served as editor of the student-owned and managed newspaper, the Cornell Daily Sun. Sale was one of the leaders of the May 23, 1958 protest against university policies forbidding male and female students fraternizing and its "in loco parentis" policy. Sale and his friend and roommate Richard Farina, and three others, were charged by Cornell. The protest was described in Farina's 1966 novel, ''Been Down So Long It Looks Like Up to Me.
Sale worked initially in journalism for the leftist journal, New Leader and the New York Times Magazine, before becoming a freelance journalist. He spent time in, and wrote his first book about, Ghana. His second book, SDS, was about the radical 1960s group Students for a Democratic Society. Subsequent books explored radical decentralism, bioregionalism, environmentalism, the Luddites and similar themes. He has continued to write for publications like The Nation, Counterpunch, The New York Review of Books, Utne Reader and Mother Jones.
In 2004 Sale, working with members of the Second Vermont Republic, formed the Middlebury Institute which is dedicated to the study of separatism, secession, and self-determination. Sale is director of the institute. In 2006 Middlebury sponsored the First North American Secessionist Convention, which attracted 40 participants from 16 secessionist organizations, and was described as the first gathering of secessionists since the Civil War. Delegates issued a statement of principles of secession which they presented as The Burlington Declaration. Sale was interviewed by the New York Times in October 2007 regarding the Second North American Secessionist Convention, co-hosted by the Middlebury Institute. Sale told the interviewer: “The virtue of small government is that the mistakes are small as well...If you want to leave a nation you think is corrupt, inefficient, militaristic, oppressive, repressive, but you don’t want to move to Canada or France, what do you do? Well, the way is through secession, where you could stay home and be where you want to be.” The convention received worldwide media attention.
In his 1990 book The Conquest of Paradise: Christopher Columbus and the Columbian Legacy, Sale argued that Christopher Columbus was an imperialist bent on conquest from his first voyage. In a New York Times book review historian and Christopher Columbus Quincentenary Jubilee Committee member William H. McNeill wrote about Sale: "he has set out to destroy the heroic image that earlier writers have transmitted to us. Mr. Sale makes Columbus out to be cruel, greedy and incompetent (even as a sailor), and a man who was perversely intent on abusing the natural paradise on which he intruded. The book Taking Sides: Clashing Views on Controversial Issues in American History presents a debate between Sale and Robert Royal, vice president for research at the Ethics and Public Policy Center who insisted that Columbus was a courageous risk-taker who advanced knowledge about other parts of the world.
Sale has described personal computers as "the devil's work" and in the past opened personal appearances by smashing one. During promotion of his 1995 book Rebels Against the Future: The Luddites and Their War on the Industrial Revolution Sale debated Newsweek Magazine senior editor and technology columnist Steven Levy "about the relative merits of the communications age. However, Sale currently uses a computer in his secessionist organizing.
News stories about the Second North American Secessionist Convention, co-sponsored by Sale's Middlebury Institute, mentioned the controversial Southern Poverty Law Center's allegations that the other co-sponsor, The League of the South, was a "racist hate group." Sale responded: "They call everybody racists. There are, no doubt, racists in the League of the South, and there are, no doubt, racists everywhere." The Southern Poverty Law Center later criticized the New York Times' October 2007 Peter Applebombe interview of Sale for not covering its allegations.