Born and raised in Needham, Massachusetts, Karlin is a University of Wisconsin—Madison Alumnus. Karlin majored in journalism and served as a reporter at the 1992 Summer Olympics in Barcelona. At The Onion Karlin is credited with coining the term "Area Man". After leaving The Onion, he moved to Los Angeles and worked as a script doctor for movies, including Ice Age, Monkeybone and Titan A.E..

In his post-The Daily Show life, Karlin has filed a lawsuit against Frappe Inc. for backing out of a book contract connected to a TV show hosted by Mario Batali and Gwyneth Paltrow . In a counter-complaint filed on behalf of Frappe, Inc., e-mails are revealed as court evidence in which Ben Karlin is self-described as an “asshole” and “difficult.” Additionally, Karlin has been involved in public conflicts with creative peers/partners such as Benjamin Wallace over ownership of production rights to a wine-fraud related movie.

In August 2007, Karlin signed a deal with HBO to produce series, specials and telepics under the banner of Picturehouse and Karlin's own company, Superego Industries. In December 2008 it was revealed that SuperEgo Industries was the company behind WonderGlen, a comedy website purporting to be the company intranet for an eccentric group of Los Angeles TV and film producers.