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. In 1958 he collaborated with Thomas Pynchon on an unproduced futuristic musical called "Minstrel Island."

Upon graduating in 1958, Sale married Faith Apfelbaum, who later worked as an editor with Thomas Pynchon, Kurt Vonnegut, Joseph Heller and Amy Tan. Faith died in 1999.

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 Ghana and wrote his first book about it. 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. Sale presented public affairs programming for WBAI in the early 1980s and has made appearances on alternative radio over the years.

Sale has been described as "one of the intellectual godfathers of the secessionist movement." He argues that the major theme of contemporary history, from the dissolution of the Soviet Union to the expansion of United Nations membership from 51 in 1945 to 192 nations today, is the breakup of great empires. Some on both left and right call for smaller, less powerful government.

In 2004, Sale and 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 American Civil War. Delegates issued a statement of principles of secession which they presented as "The Burlington Declaration."

In October 2007, the New York Times interviewed Sale about 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.

Sale wrote the foreword to Thomas Naylor's 2008 book Secession: How Vermont and all the Other States Can Save Themselves from the Empire." Sale continues to speak on secession and other issues around the nation.

In 1995, Sale made a public bet with Kevin Kelly that by the year 2020, there would be a convergence of three disasters: Global currency collapse, significant warfare between rich and poor, and environmental disasters of some significant size. The bet was turned into a claim on the FX prediction market, where the probability has hovered around 25%.

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 member of the Christopher Columbus Quincentenary Jubilee Committee 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 with Newsweek Magazine senior editor and technology columnist Steven Levy "about the relative merits of the communications age".

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.