His 1960 comedy album, The Button Down Mind of Bob Newhart, went straight to number one on the charts, beating Elvis Presley and the cast album of The Sound of Music. Button Down Mind received the 1961 Grammy Award for Album of the Year. Newhart also won Best New Artist, and his quickly-released follow-on album, The Button-Down Mind Strikes Back, won Best Comedy Performance - Spoken Word that same year.

Newhart's success in stand-up led to his own NBC variety show in 1961, The Bob Newhart Show. The show lasted only a single season, yet earned Newhart an Emmy Award nomination and a Peabody Award. The Peabody Board cited him as:

In 2001, Bob made an appearance on MAD TV (Season 6), playing a psychiatrist who yells "Stop it!" in a very memorable skit. It is widely regarded as one of the funniest bits ever on the show.

He also guest-starred on ER in a very rare dramatic role which earned him an Emmy Award nomination, his first in nearly twenty years. In 2005 he began a recurring role in Desperate Housewives as Morty, the on-again/off-again boyfriend of Sophie (Lesley Ann Warren), Susan Mayer's (Teri Hatcher) mother.

Newhart is known for his deadpan delivery and a slight stammer which early on he incorporated into the persona around which he built a successful career. On his TV shows, although he got his share of funny lines, often he worked in the Jack Benny tradition of being the "straight man" while the sometimes somewhat bizarre cast members surrounding him got the laughs.

Two of Newhart's most memorable roles were in two very different military-themed films, the 1962 film Hell Is for Heroes, and his portrayal of Major Major Major Major in the 1970 film version of Catch-22.