McGinniss graduated from the College of the Holy Cross in 1964 and became a general assignment reporter at the Worcester Telegram in Worcester, Massachusetts. Within a year he left to become a sportswriter for The Philadelphia Bulletin. He then moved to The Philadelphia Inquirer as a general interest columnist. McGinniss became an overnight success when his first book, The Selling of the President, landed on The New York Times bestseller list when he was 26 years old, making him the youngest living writer with that achievement. The book described the marketing of Richard Nixon during the 1968 presidential campaign.

After the success of his book in 1968, McGinniss left the Inquirer to write books full-time. He next wrote a novel, The Dream Team. It was followed by Heroes, and Going to Extremes, a nonfiction account of his year exploring Alaska.

In 1979 he became a writer-in-residence at the L.A. Herald Examiner. Next came the McGinniss trilogy of true crime books, Fatal Vision, Blind Faith and Cruel Doubt. All three books were made into TV miniseries. His 1983 account of the Jeffrey MacDonald murder case, Fatal Vision, was a best-seller. MacDonald sued McGinniss in 1984, alleging that McGinniss pretended to believe MacDonald innocent after he came to the conclusion that MacDonald was guilty, in order to continue MacDonald's cooperation with him. After a six-week civil trial that resulted in a hung jury, McGinniss's publisher's insurance company chose to settle out of court with MacDonald for an undisclosed amount. In her book The Journalist and the Murderer, Janet Malcolm used the McGinniss-MacDonald trial to explore the problematic relationship between journalists and their subjects.

The Last Brother: The Rise and Fall of Teddy Kennedy (1993) brought McGinniss more controversy. William Manchester, the author of The Death of a President (1967) referred to parts of The Last Brother as plagiarisms of his own book about the Kennedys. Another prominent critic, Doris Kearns Goodwin, a known plagiarist, suggested that some of his writing came close to plagiarism, although this was never substantiated.

In 1995, McGinniss sat through the O. J. Simpson trial, expecting to write a book about it, but returned the $1 million advance after Simpson was acquitted, saying the trial had been "a farce." His next book, the critically acclaimed The Miracle of Castel di Sangro, followed the fortunes of an Italian soccer team from a tiny town during one dramatic season in the big leagues.

The Big Horse was published in 2004. In his most recent book, Never Enough, McGinniss returned to his study of the dark side of the American family with a nonfiction account of the murder of investment banker Robert Kissel by his wife Nancy in Hong Kong.

In 2009 McGinniss began writing about the rise of Alaska governor and Republican Vice-Presidential candidate Sarah Palin. He published a controversial article, "Pipe Dreams", in the April 2009 issue of Conde Nast's now-defunct Portfolio and in September he bid $60,101.01 on Ebay to dine with Palin. Cathy Maples of Huntsville, Alabama, won the Ebay auction with a $63,500 bid.

McGinniss rented the house next door to Palin in Wasilla, Alaska for five months, Palin has also stated: "Wonder what kind of material he'll gather while overlooking Piper's bedroom, my little garden, and the family's swimming hole?". In May 2010 he threatened an ABC News reporter with arrest for invasion of privacy and trespassing for knocking on the door of his rented Wasilla home.

On a June 1, 2010 appearance on NBC's Today Show, McGinniss told host Matt Lauer that Palin was using the same tactics that the Nazis had used against their foes in the 1930s. The book is reportedly scheduled to be published by Broadway/Random House in 2011. McGinniss told Lauer that he is not stalking Palin. In response to McGinniss' interview on The Today Show, Palin wrote on her Facebook page, “When I say or write “leave my kids alone,” it means simply that: let my kids have a fun summer without having a “journalist” 15 ft from their play area. How that equates me with the Nazis is quite beyond me.”