- Roseanne Barr as Roseanne Conner
- John Goodman as Dan Conner
- Laurie Metcalf as Jackie Harris
- Sara Gilbert as Darlene Conner (16 episodes)
- Michael Fishman as D.J. Conner
- Lecy Goranson as Becky Conner (10 episodes)
- Johnny Galecki as David Healy (23 episodes)
- Glenn Quinn as Mark Healy (17 episodes)
- Estelle Parsons as Beverly Harris (12 episodes)
- Sarah Chalke as Becky Conner (4 episodes)
- Michael O'Keefe as Fred (3 episodes)
- Cole and Morgan Roberts as Jerry Conner
- Martin Mull as Leon Carp (8 episodes)
- Sandra Bernhard as Nancy Bartlett (4 episodes)
- Fred Willard as Scott (3 episodes)
- James Pickens, Jr. as Chuckie Mitchell (2 episodes)
- Adilah Barnes as Anne-Marie Mitchell (2 episodes)
- Shelley Winters as Nana Mary (2 episodes)
- Despite not being apart of the main cast, David Healy and Mark Healy appear in more episodes than Darlene and Becky.
- David Healy is only absent in two episodes; "The Last Date" and the finale "Fights and Stuff".
- Both Sarah Chalke and Lecy Goranson appear as Becky in the same episode ("Shower the People You Love with Stuff"). Sarah Chalke also appears in "Halloween: the Final Chapter", but doesn't play Becky.