Sayles was born in Schenectady, New York, the son of Mary (née Rausch), a teacher, and Donald John Sayles, a school administrator. Both of Sayles’s parents were of half-Irish descent and Catholic. He attended Williams College with frequent collaborators Gordon Clapp and David Strathairn, as well as his longtime partner, Maggie Renzi. Sayles earned a B.A. in psychology in 1972.

After college, Sayles moved to Boston where he worked a variety of blue-collar jobs while writing short stories for The Atlantic. These writings culminated in his first novel, The Pride of the Bimbos, published in 1975.

Like Martin Scorsese and Francis Ford Coppola, Sayles began his film career working with Roger Corman. In 1979, Sayles used $30,000 he earned writing scripts for Corman to fund his first film, Return of the Secaucus 7. To make the film on a limited budget, he set the film in a large house so that he did not have to travel to or get permits for different locations, set the story over a three-day weekend to limit costume changes, and wrote about people his age so he could cast his friends in it. The film received near-unanimous critical acclaim at the time and has held its reputation. In November 1997, the National Film Preservation Board announced that Return of the Secaucus 7 would be one of the 25 films selected that year for preservation in the National Film Registry at the Library of Congress.

In 1983, after the films Baby It’s You (starring Rosanna Arquette) and Lianna (a story in which a married woman becomes discontented with her marriage and falls in love with another woman), Sayles received a MacArthur Fellowship. He put the money into the science fiction feature The Brother from Another Planet, a film about a three-toed humanoid who escapes bondage on another world and crashes-lands in New York harbour; because he is Africanoid in appearance, he finds himself at home among the people of Harlem, being pursued by European-looking alien enslavers men in black.

In 1983, Sayles received the John D. MacArthur Award, given to 20 Americans in diverse fields each year for their innovative work. He has also been the recipient of the Eugene V. Debs Award, the John Steinbeck Award and the John Cassavetes Award. He was honored with the Ian McLellan Hunter Award for Lifetime Achievement by the Writers Guild of America (1999).

In 1989, Sayles created and wrote the pilot episode for the short-lived television show Shannon’s Deal about a down-and-out Philadelphia lawyer played by Jamey Sheridan. Sayles received a 1990 Edgar Award for his teleplay for the pilot. The show ran for 16 episodes before being cancelled in 1991.

In early 2003, Sayles signed the Not In Our Name “Statement of Conscience” (along with Noam Chomsky, Steve Earle, Brian Eno, Jesse Jackson, Viggo Mortensen, Bonnie Raitt, Oliver Stone, Marisa Tomei, Susan Sarandon and others) which opposed the invasion of Iraq

In February 2009, Sayles was reported to be writing an HBO series based on the early life of Anthony Kiedis of the Red Hot Chili Peppers. The drama, tentatively titled Scar Tissue, centers on Kiedis’s early years living in West Hollywood with his father. At that time, Kiedis’s father, known as Spider, sold drugs (according to legend, his clients included The Who and Led Zeppelin) and mingled with rock stars on the Sunset Strip, all while aspiring to get into show business.

In February 2010, Sayles began shooting his 17th feature film, the historical war drama Amigo, in the Philippines. The film is a fictional account of events during the Philippine–American War, with a cast that includes Joel Torre, Chris Cooper, and Garret Dillahunt.

His novel A Moment in the Sun, set during the same period as Amigo, in the Philippines, Cuba, and the U.S., was released in 2011 by McSweeney’s. It includes an account of the Wilmington Insurrection of 1898 in North Carolina, the only coup d’état in United States history in which a duly elected government was overthrown.