Born to Jewish parents Michael and Linda (née Kaufman), Portnoy grew up in Swampscott, Massachusetts, where he attended Swampscott High School. One of his classmates was ESPN’s Todd McShay. Portnoy began attending the University of Michigan in 1995, graduating with a degree in education.

Following graduation in 1999, Portnoy moved to Boston and began working at Yankee Group, an IT market research firm.

Portnoy is Jewish. He married Renee Satherthwaite in 2009. In January 2017, Portnoy separated from his wife.

In 2013, Portnoy launched an unsuccessful campaign to become the Mayor of Boston following the retirement of Thomas Menino. After raising over $17,000 in campaign contributions, he failed to submit enough nomination signatures to qualify for the election. During the race, Portnoy identified as a Libertarian.

On May 12, 2015, Portnoy was arrested by New York City police after he and three Barstool employees handcuffed one another on the floor of NFL headquarters. The protest was a reaction to Deflategate.

After four years, Portnoy left the company to begin what would eventually become Barstool Sports. On January 7, 2016, Portnoy announced The Chernin Group had purchased a majority stake of Barstool and the headquarters would be moving to New York City. In 2020, Penn National Gaming purchased a 36% stake in Barstool Sports for $163 million. Following the sale, The Chernin Group maintained a 36% stake in the company, while Portnoy continues to run the site and retains creative control over content.

One Bite with Davey Pageviews is an internet show that Portnoy created, which consists of him reviewing pizza. Portnoy began his goal of reviewing every pizza place in Manhattan in 2017. While many videos include only Portnoy, celebrities and athletes often also appear as guests.

In August 2019, the National Labor Relations Board commenced an investigation into Portnoy on charges that he illegally threatened to fire his workers if they unionize. In December 2019, Portnoy settled with the National Labor Relations Board. The informal settlement required Portnoy to delete his threatening tweets and remove any potential anti-union material created by Barstool Sports.