Ruby Jean Granny Cuyler is both the oldest and wisest of the Cuylers. She is Rusty, Lil and Early's ancestor, but exactly how she is related is unknown for sure. She is often seen being blown out or knocked out of her walker due to Early or Rusty's destructive actions.

She is prone to becoming confused about her current situation and whereabouts due to her extreme senile dementia. Granny is also a nymphomaniac who propositions most of the series' characters for sex at one point or another. It is also implied that she has an incestuous relationship with Lil (also apparently without consent), and has encouraged Rusty to scratch her genitalia. She suffers from various health problems, including a failing gallbladder, but doesn't die which could be due to her repeated attempts to hit-on Squid Jesus, who at one point ordered angels to restore her to life just so he wouldn't have to deal with her or her unwanted advances. She is apparently a published author, her book E Is for Equine making a brief appearance in episode five of Season Two. In Holodeck Redneck, her holographic fantasy is killing herself with a shotgun and being buried in the cemetery. As of the events of Dewey Two-ey, she is married to Boyd's Possible Stepfather Dewey Duvall.