According to Kevin Clash, the decision to have Clifford as host was made because Jim Henson had requested, in the event of his passing, that any future Muppet Show should not be hosted by Kermit the Frog.
The Muppets who made their debuts on the show included Pepe the King Prawn, Johnny Fiama, Fiama's monkey companion Sal Manella, Bobo the Bear, Seymour the elephant, Spamela Hamderson, and Bill the Bubble Guy. Only the first four characters would appear in later productions.
ABC put Muppets Tonight (1996) on temporary hiatus following a controversy involving Sandra Bullock (1996), which featured a subplot where an unknown, incognito character called in a bomb threat to the Muppet studios. Although intended to parody Speed (1994), this episode was originally scheduled to air on Friday, April 19, 1996, which happened to be the 1st anniversary of the Oklahoma City Bombing. In response to negative publicity, ABC pulled the episode from its lineup days before it was scheduled to premiere, citing the unfortunate, but unintentional, coincidence as the reason for canceling the show for the night. The episode eventually aired on ABC in its entirety on June 23, 1996.
The director of Muppets Tonight is named Nigel. This is a reference to a Muppet of the same name who was the host of one of the original Muppet Show pilot episodes [The Muppet Show: Sex and Violence (1975)], and who later became the orchestra conductor on the show itself.
The first episode aired on ABC on March 8, 1996, three weeks after Muppet Treasure Island (1996) premiered in theaters.