The show centers on Robot Jones, a robotic 12-year-old attending a suburban middle school. This series was produced using traditional hand-painted cels at a time when most TV cartoons were in the process of switching to digital animation (possibly due to the fact that this series takes place in the 1980s).
- Robot Electro Jones (voiced by a text-to-voice program in season one and Bobby Block in season two) is a robot who does whatever he can to fit in the human society, which can sometimes go awry. Whenever the day ends he adds to his memory called Data Log Entry something he learns through the experience. His brain is a giant light bulb.
- Dad Unit is Robot's father. When he says something, he often says it three times; one example would be "Listen to your mother! Listen to your mother! Listen to your mother!" as said in the inaugural episode. He has one hand, wears a tie and in his focus on tasks he often gets into shenanigans such as smashing through walls. He is voiced by Macintalk's 'Ralph' voice, which was also used for the voice of Auto in WALL-E.
- Mom Unit (voiced by Grey DeLisle) is Robot's mother. She is pink in color and her hands look like the ends of a gas pump's hose which she uses for giving fuel to her fellow units. She seems to generally have a no-nonsense attitude.
- Timothy "Socks" Morton (voiced by Kyle Sullivan) is the best friend of Robot Jones. He is quite a fanatic to rock music. He has blond curly hair and wears a green jacket.
- Charles "Cubey" Cubinacle (voiced by Myles Jeffrey) is the shorter friend with dark, straight hair, sunglasses with window blinds for lenses, and roller skates. He is a video game lover and wears a Pac-Man T-Shirt.
- Mitchell "Mitch" Freeman Davis (voiced by Gary LeRoi Gray) is a lad often seen wearing headphones, a red sweater and sandals. His eyes are obscured by his long hair. In "Scantron Love", his last name was Davis.
- Lenny and Denny Yogman (voiced by Josh Peck and Austin Stout respectively) are the notorious young genius twins of the show. They wear red hats that resembles the 1980s band Devo's energy dome hats, yellow shirts, and black sneakers. Lenny is tall while Denny is short. They do whatever they can to take Robot's brain.
- Shannon Westerburg (voiced by Grey DeLisle) is a girl whom Robot loves because she has more mechanical attachments than any human he has ever seen, specifically a large orthodontic appliance and a prosthetic leg. She is unaware that Robot has a crush on her and typically finds him more of an annoyance than anything else. Shannon talks with a lisp.
- Mr. McMcMc (voiced by Maurice LaMarche in the pilot and Rip Taylor in the series) is Robot Jones' math teacher.
- Clancy Q. Sleepyjeans (voiced by David Koechner) is the school janitor.
- Principal Madman (voiced by Maurice LaMarche in the pilot and Jeff Glen Bennett in the series) is the principal of Polyneux Middle School. His mustache resembles that of Adolf Hitler's; as such, he is very tyrannical to his students.
- James Nob (voiced by Gedde Watanabe) is the tyrant owner of Nob's Arkaid, where Robot and his friends hang out. he keeps telling kids that they're breaking his arcade mechines, every time they play them. In "Hookie 101", it is revealed that he has a discount on game tokens during school.
- Gramps Unit (voiced by Macintalk's 'Zarvox') is Robot Jones' grandfather. Gramps Unit sounds like Robot Jones' father, but he could be the dad of either Dad Unit or Mom Unit.
- Mr. Workout (voiced by Dee Bradley Baker) is the Gym teacher of Polyneux Middle School.
- As of 2016, Cartoon Network still has no plans on releasing Whatever Happened to... Robot Jones? on DVD or iTunes, despite both Cow and Chicken and Evil Con Carne being on iTunes as of August 2018.
- Robot Jones made a returning cameo in the OK KO episode, Crossover Nexus; where he was turned into stone like other Cartoon Network characters, he also appeared as one of Ben Tennyson's transformations.
- Whatever Happened to... Robot Jones? never had any re-runs on sister channel, Boomerang, which is very strange because there have been a lot of Cartoon Network shows that never had re-runs on the sister channel itself. examples: SquirrelBoy, Megas XLR, Class of 3000.