After graduating, Nayyar found work doing American television ads and plays on the London stage. He first gained attention in the US for his role in the West Coast production of Rajiv Joseph's 2006 play Huck & Holden where he portrayed an Indian exchange student anxious to experience American culture before returning home. In 2006, Nayyar teamed up with Arun Das to write the play Cotton Candy, which premiered in New Delhi to positive reviews. Nayyar made a guest appearance in the CBS drama NCIS in the episode "Suspicion" (season 4, episode 12), in which he played Youssef Zidan, an Iraqi terrorist. His agent heard about a role for a scientist in an upcoming CBS pilot and encouraged him to audition for the part. This led to his casting in the sitcom The Big Bang Theory, on which he plays astrophysicistRajesh Koothrappali.
In 2011 he co-hosted the Tribute to Nerds show with co-star Simon Helberg at the Just for Laughs comedy festival. As of 2012, he is working on his first movie, Dr. Cabbie, in which he will be opposite famous Indian actress Katrina Kaif's sister, Isabell. He is shooting Dr. Cabbie in Toronto, Canada.