Carol Ann Susi's agent, Pam Ellis-Evenas, said the actress died in Los Angeles on Tuesday after a brief battle with cancer. She was 62.
The veteran character actress has made numerous guest appearances on TV shows since the 1970s.
On the The Big Bang Theory, she wasn't seen on camera as the mother of Simon Helberg's character, Howard, but her character's loud voice with a Brooklyn accent was instantly recognizable.
The executive producers of the CBS sitcom say Susi was a beloved member of the Big Bang Theory family, and they praised her "immense talent and comedic timing".
Susi is survived by her brother, Michael Susi, and his wife, Connie.
Stars of the hit show took to Twitter to express their grief after the news broke.
Beloved Carol Ann Susi passed away, yes. The voice of Mrs wolowitz. Oh Carol Ann. http://t.co/cx8h9pUQ7s
— Mayim Bialik (@missmayim) November 12, 2014
So grateful to have known Carol Ann Susi who brought laughter & light with her always. She'll forever be in my heart. http://t.co/ecSsW7buPQ
— Melissa Rauch (@MelissaRauch) November 12, 2014
My heart is broken. I will miss your smile. Your spirit is forever with us. http://t.co/AOmLTEV0ZF
— Kunal Nayyar (@kunalnayyar) November 12, 2014