Each show begins with the reggae theme song, "Everyday, when you're walkin' down the street, everybody that you meet has an original point of view".
- Arthur, a third-grade boy aardvark
- D.W., his sister (4 3/4 years old)
- Buster, Arthur's rabbit friend
- Brain, an intelligent bear (once voiced by Steven Crowder
- Binky, a British Bulldog and former bully
- Muffy, a wealthy monkey
The show met some controversy in the 22nd-season premiere, "Mr. Ratburn and the Special Someone", when one of the mainstay characters, Mr. Ratburn, not only came out as homosexual (marking the first instance of homosexuality in the series since the spinoff show Postcards from Buster), but also ended up entering a homosexual "marriage", with such an event being portrayed positively. The episode was skipped in Alabama and Arkansas.