Peretti was born in California and raised in Oakland, California. His father, a criminal defense lawyer and painter, is of Italian and English descent and his mother (née Cherkin), a schoolteacher, is Jewish. His stepmother was African-American. He attended The College Preparatory School in Oakland, followed by the University of California, Santa Cruz, where he graduated with a degree in environmental studies in 1996. He taught computer science classes at Isidore Newman School in New Orleans, in the mid-1990s. He completed a postgrad at the MIT Media Lab.

Peretti co-founded The Huffington Post along with Kenneth Lerer, Andrew Breitbart and Arianna Huffington in 2005. He left The Huffington Post in 2011 after it was bought by AOL for $315 million.

In 2005, Peretti hosted the Contagious Media Showdown at Eyebeam in New York City, where he worked as director of the R&D Lab from 2001 to 2006. During the process Peretti developed the concept of the “Bored-at-Work Network”, which he supposes to be larger than some major television network audiences.

Peretti founded the “Internet popularity contest” site BuzzFeed in November 2006. After leaving The Huffington Post, Peretti began working at BuzzFeed full-time. While originally known for its mix of internet memes and lists, the site was the first to break the news that John McCain would endorse Mitt Romney in the 2012 Republican Primary. The site continued to grow afterward, raising over $35 million in funding from investors the next year. In August 2014, the site raised another $50 million from the venture capital firm Andreessen Horowitz, more than doubling its previous rounds of funding. The site was valued at nearly $1 billion by Andreessen Horowitz.

In 2019, Peretti announced that BuzzFeed would be cutting its overall workforce by 15 percent. Peretti said he wanted to reduce costs without resorting to additional fundraising. Its remaining workforce then officially unionized, their first successful fight being over laid-off staffers getting their earned paid time off.