Rue is the main character of Euphoria. She is attracted to girls and falls deeply in love with Jules. Rue is intelligent, sarcastic, and incredibly observant, but she struggles with addiction and mental health issues. Rue overdosed and was sent to rehab. after she returns home from rehab, though she is not fully committed to staying sober. As a child, Rue was diagnosed with several mental health conditions. She was extremely close to her father, and his illness and death devastated her. After losing him, she turned to unhealthy coping mechanisms. Despite her mistakes, Rue genuinely loves her family and friends and wants to be better, even when she doesn't know how.

Jules is a transgender girl who recently moved to town with her father. She is artistic, emotional, and always searching for freedom and self-discovery. Jules often dreams of escaping her current life and starting over somewhere new. Growing up, Jules struggled with her mental health and spent time in psychiatric treatment. She wants to be accepted for who she truly is and often seeks excitement and new experiences. Her relationship with Rue becomes one of the most important and emotional storylines in the series.

Nate is the star football player at school and comes from a wealthy, respected family. He appears confident, attractive, and successful, but underneath he is controlling, angry, and deeply insecure. As a child, Nate discovered secrets about his father's private life that affected him. Combined with intense pressure to be perfect, these experiences shaped many of his fears, insecurities, and destructive behaviors.

Maddy is glamorous, confident, and fearless. She knows how to command attention and refuses to let people disrespect her. Growing up, she watched her parents fight constantly and decided she wanted more from life. Beneath her bold exterior, Maddy wants genuine love, security, and independence. She has an on and off relationship with Nate that becomes a major storyline.

Cassie is sweet, and deeply sensitive. She wants to be loved and often bases her self worth on how other people see her. When she was younger, Cassie had a close relationship with her father. After his addiction led him to leave the family, she was heartbroken. In her teenage years, she received a lot of attention because of her appearance, which caused her to seek validation in relationships.