From 2007 to 2019, he played Howard Wolowitz on the CBS sitcom The Big Bang Theory (2007–2019), and won the Critics' Choice Television Award for Best Supporting Actor in a Comedy Series for the role.

His performance as Cosmé McMoon in the film Florence Foster Jenkins (2016), received a nomination for the Golden Globe Award for Best Supporting Actor – Motion Picture.

[10] In 2007, the two starred together in Derek and Simon: The Show, a web series they created with comedian Bob Odenkirk for the comedy website Super Deluxe.

In 2006, he appeared in a series of comical TV commercials for Richard Branson's UK 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.

[5][11] He appeared as the character Moist in Dr. Horrible's Sing-Along Blog, and had a small role in the pilot episode of the Judd Apatow-produced sitcom Undeclared.

In 2016, Helberg starred alongside Meryl Streep and Hugh Grant in Florence Foster Jenkins, directed by Stephen Frears; he played pianist Cosmé McMoon and his performance was nominated for the Golden Globe Award for Best Supporting Actor – Motion Picture.