Varghese is Indian American, the son of Malayali immigrant parents from Kerala and grew up in Garland, Texas, a suburb of Dallas. He earned a bachelor's degree in radio, television and film from the University of North Texas in 2000. In college, he spent his junior year at William Patterson University of New Jersey, during which he interned on Sally Jesse Raphael's talk show. His sister is an Episcopalian priest at Columbia University in New York.
Varghese, who began doing stand-up in 2001, opened for Canadian-born comedian Russell Peters in a short theater-tour through Los Angeles, San Francisco, Boston and New York in 2005. That led to his headlining a 16-city Gurus of Comedy tour in the spring of 2006.