A close friend of Andrew and Nick in Big Mouth, Jessi Glaser (Jessi Klein) is just another girl trying to navigate the beginning of her teen years. After getting her period for the first time on a school field trip, she meets the Hormone Monstress and shenanigans ensue. One of her first acts of pubescent rebellion is in buying a scandalous red push-up bra.

In Big Mouth, Andrew Glouberman is an awkward Jewish middle schooler figuring out things with his best friend Nick Birch as they goes through puberty. He develops crushes, an obsession with pornography, and soon enough, his overactive hormones manifest as a profane, sex-obsessed monster.

In Big Mouth, Lola Skumpy (voiced by Nick Kroll) is one of the popular girls at school. She has a thing for thick Jewish boys, and dates Andrew Glouberman. Unfortunately, when he breaks up with her, she breaks his wrist.

In Big Mouth, Missy (voiced by Jenny Slate) is a girl who was once girlfriend to Andrew Glouberman.

In Big Mouth, the youngest boy in a violently dysfunctional family, Jay Blizerian (Jason Mantzoukas) is a friend of Andrew, Nick, and Jessi. Jay is passionate about magic tricks, his pillow, and not getting pummeled by his older brothers. Later in the first season, Jay and Jessi start to become closer romantically.