Helberg attended middle and high school at the Crossroads School in Santa Monica, California, with Jason Ritter, who later became his roommate at New York University. He attended New York University"s Tisch School of the Arts, where he trained at the Atlantic Theater Company.
He has appeared on the sketch comedy series MADtv and is also known for his role as Moist in Joss Whedon"s web miniseries Doctor Horrible"s Sing-Along Blog. Since the early 2000s, Helberg performed with comedian Derek Waters as the sketch comedy duo Derek & Simon. In 2007, the two starred together in Derek & Simon: The Show, a web series they created with comedian Bob Odenkirk for the comedy website Super Deluxe.
They also made two short films "Derek & Simon: The Pity Card" (co-starring Zach Galifianakis and Bill Hader) and "Derek & Simon: A Bee and a Cigarette" (co-starring Casey Wilson and Emily Rutherfurd) and had a pilot deal with Home Box Office in 2005.
One of Helberg"s earliest jobs in television was briefly joining the cast of MADtv for one season in 2002. Helberg appeared in the 2002 feature film Van Wilder as one of the geeky students for whom Van Wilder was throwing a party.
He had a minor role in the 2003 movie Old School. In 2004, he was in two episodes of Reno 911!: Student Driver in Raineesha X and Hooker Buying Son in Not Without My Mustache.
He had a small role in the sixth episode of Quintuplets, Get a Job, as a man called Neil working behind the counter at a shoe shop where Paige and Patton were working.
In 2004, he appeared in the film A Cinderella Story, starring Hilary Duff and Chad Michael Murray. Helberg played the minor role of Simon in George Clooney"s 2005 film Good Night, and Good Luck, where he had one line. In 2005, he had a bit part on Arrested Development as Jeff, an employee of the film studio where Maeby worked.
From 2006-2007, he had a minor supporting role as Alex Dwyer in the drama Studio 60 on the Sunset Strip.
In 2006, he appeared in a series of comical television commercials for Richard Branson"s United Kingdom financial services company Virgin Money. He played a small role in the 2007 film Walk Hard: The Dewey Cox Story as a Jewish record producer.
He appeared as the character Moist in Doctor Horrible"s Sing-Along Blog, and had a small role in the pilot of the Judd Apatow-produced sitcom Undeclared. In the 2009 Coen brothers film A Serious Manitoba, he played junior Rabbi Scott Ginsler.
He had a minor role in the season 4 finale of The Guild as one of the Game Masters.
In 2007, Helberg was cast as Howard Wolowitz, in the Columbia Broadcasting System comedy series The Big Bang Theory.