- Thomas "Tommy" Malcolm Pickles (voiced by E.G. Daily): The most bravest and adventurous baby, always encouraging the group to go on many of their adventures.Generally considered the diaper leader. Tommy is named for the first son of Paul Germain, one of the show's creators.
- Dylan "Dil" Prescott Pickles (voiced by Tara Strong): Tommy's younger brother, a true baby (i.e. not a toddler like the other children (a.k.a. babies)). Introduced in the first Rugrats movie.
- Charles "Chuckie" Crandall Finster III (voiced by Christine Cavanaugh (1991–2001) and Nancy Cartwright (2002–present): Tommy's loyal friend, Afraid of everything, especially the "guy on the oatmeal box". In one episode, it is revealed that he is left-handed.
- Phillip "Phil" Richard Bill DeVille & Lillian "Lil" Marie Jill DeVille (voiced by Kath Soucie): Twins (boy and girl) that have everything in common. Both enjoy playing in mud and like to eat worms and insects in "The Worm Pit", they don't care about their nephews. They are always bickering, but cannot be separated.
- Angelica Charlotte Pickles (voiced by Cheryl Chase): Tommy and Dil's cousin who always bosses the "babies" around, being the oldest. Enjoys lying to the toddlers, distorting their perception of reality. Acts perfect towards the adults but is generally mean to the babies.
- Kimi Watanabe-Finster (voiced by Dionne Quan): Chuckie's younger step-sister, introduced in the second Rugrats movie, Rugrats in Paris. Kimi is a very happy girl (years later, a teenager) who always is smiling. She and her mother are Japanese.
- Susanna "Susie" Yvonne Carmichael (voiced by Cree Summer): A neighborhood tomboy who is about Angelica's age. When around, Susie often stands up to Angelica when she taunts the young toddlers. She and her family are African-American.
- Stuart "Stu" Pickles (voiced by Jack Riley): Tommy and Dil's father and brother of Drew. Absent-minded inventor. Married to Didi.
- Diane 'Didi' Kropotkin Kerpackter-Pickles (voiced by Melanie Chartoff): Tommy and Dil's mother. A part-time schoolteacher and married to Stu.
- Louis Kalhern "Lou" "Grandpa" Pickles II (voiced by David Doyle (from 1991, until his death in 1997), and Joe Alaskey (1997–2004)): Tommy, Dil and Angelica's grandfather and Stu and Drew's father. Lived with Stu's family for the first few seasons and often babysat the children.
- Louise "Lulu" Jonston (voiced by Debbie Reynolds): Lou's second wife; he met her in the hospital where she works as a nurse. Also Tommy, Dil, and Angelica's grandmother and Stu and Drew's stepmother.
- Andrew 'Drew' Pickles (voiced by Michael Bell): Angelica's father and Stu's brother. An investment banker (much like Mr. George Banks from Mary Poppins); married to Charlotte.
- Charlotte Cilia McSell (voiced by Tress MacNeille): Angelica's workaholic mother. CEO of her own company (just like Donald Trump) and married to Drew. She tries to be a good mother, but is usually sidetracked by business interests.
- Elizabeth 'Betty' Gizelle (voiced by Kath Soucie): Phil and Lil's tomboyishly beautiful mother. Quite the jock and women's-libber. Married to Howard.
- Howard 'Howie' DeVille (voiced by Phil Proctor, formerly of Firesign Theatre): Phil and Lil's father. Often overpowered by and cringing towards his wife, Betty.
- Charles Norbert 'Chas' Finster Sr. (voiced by Michael Bell): Widower; Chuckie's father, from whom he inherited his adenoidal whine. Married Kira in the second Rugrats movie. Kimi's step-father. Runs the Java Lava Coffee House.
- Kira Watanabe-Finster (voiced by Julia Kato): Kimi's mother and Chuckie's step-mother. Married Chaz in the second Rugrats movie. Operates the Java Lava Coffee House with her husband.
- Lucia "Lucy" Carmicheal (voiced by: Cheryl Carter (1992, 1997-), Lisa Dinkins (1993), Hattie Winston (The Rugrats Movie): Susie's mother and Randy's wife. She is a Harvard-educated "wonder mom" and does a lot of cool things. She is also a Doctor. She delivered Dil.
- Randall Randolph “Randy” Carmichael (voiced by: Ron Glass): Married to Lucy Carmichael & is Susie's father. Randy is a writer for the famous Dummi Bears Show.
- Melanie Melissa "Melinda" Finster (voiced by Kim Cattrall): is Chuckie's late birth-mother. She loved flowers, and she died a few months after Chuckie's birth, long before the show began. She is only seen in flashbacks, although she is referenced several times in the series.
- Jonathan Kraskell (Voiced by Rene Auberjonois in 1995 and Dan Castellaneta from 1998 until the series end): is Charlotte's meek assistant, whom she constantly yells at.
- Frederick Joseph “Freddy” Gizelle (voiced by: Rodger Bumpass): Uncle Freddy is Phil and Lil's uncle and Betty's brother.
- Spike (not voiced in the TV show, but voiced by Bruce Willis only in Rugrats Go Wild): The Pickles' brown hound dog. Tommy deeply admires him.
- Fifi (not voiced): Purple poodle which Spike fell in love with in the second Rugrats movie. Now, lives with the Finsters.
- Puppy and Peppy (not voiced): Purple and brown (respectively) puppies adopted by the Drew Pickles and Chaz Finster households. Probable (one is led to believe) offspring of a union between Spike and Fifi.
- Fluffy (not voiced): Angelica's cat who Angelica loves dearly, but who always causes trouble for the others, particularly Spike.
- Reptar (not voiced): A big green dinosaur reminiscent of Godzilla. Tommy and the other Rugrats love him; Reptar products such as cars, clothes and candy are frequently seen on the show. Reptar was a main character in Rugrats in Paris and had his own theme park called Euro Reptarland. There was a giant Reptar robot that Stu built there too.
- Robosnail (voiced by John Lithgow): Reptar's arch enemy. Robosnail is a mechanical snail with snapping pincers. He made a special guest appearance in Rugrats in Paris, controlled by Jean Claude-Coco's assistant. Robosnail and Reptar fought throughout Paris and he wound up falling into a river.
- Thorg: a gorilla resembling King Kong. His only known quote is "Thorg hungry! Thorg want eat!"
- Mr. Friend: A robotic clown which Stu created and tested it on the babies. It is creepy and always finding the babies, attempting to "make friends" with them. Eventually buried, only to return in many smaller versions which Tommy & Chuckie destroyed.
- Taffy (voiced by Amanda Byrnes): Lulu's beautiful 16 year old grand-niece who became the 2nd babysitter for the babies or "minis" as she calls them.