In 1958, Sherry Jackson left the show and the character of Terry was temporarily written out of the show as being away at school. Terry returned, however, in 1959, this time played by actress Penny Parker. Terry spent the next season being courted by nightclub entertainer Pat Hannigan (played by Pat Harrington Jr.,) whom she eventually married. Her character then left the show for good in 1960. There were also many other regulars, including Danny's Uncle Tonoose (played by Hans Conried,) Danny's agents at various times (played by Horace McMahon, Jesse White & Sheldon Leonard) and many more. Annette Funicello also spent a season as a regular when she was cast as Gina Minelli, an Italian foreign exchange student.

The title "Make Room for Daddy" was only used during the first four seasons, then it was changed to "The Danny Thomas Show". When it entered syndication, however, all the episodes ran under the "Make Room for Daddy" title. In 1970, the Williamses returned for "Make Room for Granddaddy" which ran one brief season.

In 1957, the show switched networks from ABC to CBS. After the switch, the show finally got the ratings it deserved. Also of note, this show spawned a classic hit series; the episode 'Danny Meets Andy Griffith' was the pilot for The Andy Griffith Show. Also, such guests as Bill Dana and Joey Bishop got their own shows after appearences on The Danny Thomas Show. Bill Dana reprised his role from The Steve Allen Show, and NBC gave him his own show The Bill Dana Show in 1963 and it lasted until 1965. Joey Bishop got "The Joey Bishop Show", which aired on NBC, then CBS. It lasted from 1961 to 1965.