Mezrich is best known for his first non-fiction work, The Inside Story of Six MIT Students Who Took Vegas for Millions (ISBN 0-7432-4999-2). This book tells the story of a group of students from MIT who bet on blackjack games using a sophisticated card counting system, earning millions of dollars at casinos in Las Vegas and other gambling centers in the United States and the Caribbean. The story was made into the movie 21, released in 2008.

In 2004, Mezrich published a new book called The True Story of the Ivy League Cowboys Who Raided the Asian Markets for Millions (ISBN 0-06-057500-X). Also a nonfiction work, this book recounts the exploits of an American named John Malcolm, who was an assistant securities trader.

In 2005 Mezrich published The MIT Whiz Kid Who Brought the Casinos to Their Knees (ISBN 0060575123) a semi-sequel to Bringing Down the House. The book tells the story of another student involved in a similar Blackjack team, but one that used more advanced techniques than the ones discussed in the first book.

In 2007, Mezrich published Rigged (ISBN 0061252727) which recounts a largely fictional account of the formation of what would eventually become the Dubai Mercantile Exchange by two young visionaries, one in the New York Mercantile Exchange and the other in the Dubai Ministry of Finance.

Mezrich published a new book in July 2009 about Mark Zuckerberg, the founder of Facebook, titled The Founding Of Facebook, A Tale of Sex, Money, Genius, and Betrayal (ISBN 0385529376). It debuted at #4 on the New York Times Nonfiction Bestseller List, and #1 on the Boston Globe Nonfiction Bestseller List.

Mezrich is the co-host of season 3 of the GSN series The World Series of Blackjack and the World Blackjack Tour. He also represented Massachusetts as a contestant in the Sexiest Bachelor in America Pageant on Fox in 2000. Fatal Error is a TBS premiere movie adaptation of his second book, Reaper, starring Antonio Sabato, Jr. and Robert Wagner. Skin was originally written as an X-Files episode. Rigged was optioned by Mark Cuban's 2929 as well as "Q" a work of fiction by Mezrich. Ugly Americans has been optioned by Summit, the screenplay was written by Robert Schenkkan, Pulitzer Prize-winning writer of The Quiet American, and a draft also completed by Mezrich himself.