Casey is a smart and well-mannered teenage girl who claims to have once had a perfect life, living with her single mother Nora and her little sister Lizzie. When her mother meets and marries a lawyer named George Venturi, who happens to have three kids of his own, she is forced to move, change schools, and adjust to living with her "what Derek wants, Derek gets" stepbrother. Although Casey is very opinionated about Derek being sneaky and cruel, she herself can be selfish at times as Derek begins to rub off on her. For example, she enjoys controlling his band 'D-Rock' as the lead singer, and mocks him frequently about failing his driving test five times when she got hers before him.
Her only constant is her self-righteousness, and she often needs the school counselor to set her straight. After Casey broke up with Sam, she soon developed a crush on Max, and in the episode "It's Our Party", she is seen dancing with him. Afterward, the two start dating.
Casey is passionate about dancing, and she likes to sing and act, and her style is often described as "preppy". Her best friend is Emily Davis. Casey is a perfectionist. If things aren't perfect, she often throws a fit. In many episodes, Casey often gets angry with her boyfriend Max if he makes a mistake. Casey and Max broke up in the episode "Rumor Mill", but then they got back together at the dance in the same episode. They broke up again in the episode "Allergy Season". On her sixteenth birthday, Casey had to have an emergency appendectomy. While Casey was recovering she clearly pushed the blame on Derek without reason. Casey has hurt Derek's feelings a few times and didn't care. She made the cheerleading squad and it made Max's jealous ex-girlfriend Amy more friendly toward her.
Casey has been shown to miss Max and asks him to get back together with her. He tells her to give him some time but then declines the offer, replying that he had started seeing someone once they had broken up. In this season, a new kid named Truman is considered to be her main love interest, though she denies it whenever possible due to Truman's laid-back and egotistical personality. She kissed him in the episode "No Secrets" when Casey once again denies that she has a crush on him and Truman tells her to kiss him, as it should mean nothing if she has no feelings for him. In the episode "No More Games" she decides to give him a chance. After, she gives Truman a chance she goes tells him that she does not remember any of her first dates. Hence, Truman takes her on the worst date of her life so she would never forget it. She then tricks him and takes him on the worst date of his life. After,that she tells him about her tricking him so they kiss goodnight and laugh it off and say they will go on there real date next time. On the next episode, Truman invites Casey to go to a party in Toronto. Casey's Mom(Nora) does not approve so she sends Derek with her. Also, Casey tells her mom she will stay at her cousin Vicky's because her house is 2 hours away. At the party Truman leaves Casey alone and starts kissing her cousin, Casey spots him and starts to cry. She tells Derek and he confronts Truman. Truman apologizes but Casey doesn't buy it. When Casey gets home she tells her mom, "He is not that bad". Her mom replies,"Who, Truman?". Casey replies," No, Truman is scum. I meant Derek.". That concludes the episode and her crush on Truman.
However, in another episode, Casey didn't have anyone to go to Prom with her and gets back with Truman after Truman showed up to take her to prom.
- Emily Davis - (Shadia Simmons) Casey's best friend and next door neighbor who had a major crush on Derek, but soon ended when Derek revealed that he only went out with Emily to make Casey jealous. She seems to think popularity is more important than her friends, but is always there when Casey needs her. She has a little brother named Dimmy who is friends with Marti.
- Sam - (Kit Weyman) Derek's best friend who had a crush on Casey but is constantly being influenced by Derek. Casey also had a crush on Sam. In the episode "Male Code Blue" they finally decide to go steady, but break up in the episode "Middle Man-ic". He is one of the guitarists in the band, D-Rock. He was Casey's first boyfriend (during the show).
- Mr. Paul Greebie - (Arnold Pinnock) Casey's laid-back Guidance Counselor who is always ready to give Casey advice. Although Casey has asked him, he won't tell her what to do, only give suggestions. He is also very clumsy. Once, when tipping his chair back to far, he fell and landed in the trash can. He is also very disorganized, and is also the computer/science teacher in addition to being Guidance Counseler.
- Max Miller - (Robbie Amell) Casey's second ex-boyfriend. He is a jock, being quarterback of the school football team. He is revealed to be quite impolite sometimes, for example: not giving warning to Casey when a ball was about to hit her, not holding the door open for her, and laughing at Casey's embarrassing moments. Casey and Max break up at the end of Allergy Season because Casey needed a break from her and Max so she could "find herself".
- Truman - (Joe Dinicol) A new kid in Casey and Derek's high school and Casey's love interest after Max. His cocky laid-back personality resembles that of Derek and may be the reason she denies her feelings for him, even though she has recurring dreams about him. It was revealed in "No Secrets" that prior to attending his current high school, he was kicked out of private school due to driving around his principal's car without permission.
- Noel - (Adam Butcher) Casey's new friend since "Show-Off-Tune." It is clear that he has a crush on her, but she is oblivious to it until the episode "Just Friends". They are still friends as Casey called him and asked him to prom.
While Casey has a lot to deal with in her life - living with George, Edwin, and Marti; trying to fit in at a new school; and figuring out where she and her sister stand in this new family; it all pales in comparison to her single biggest challenge, the show's namesake, "Life with Derek". She doesn't hate Derek,- she just didn't want to leave her old life and cram into his house. Everyone in the Venturi house has always been expected to play by Derek's rules, and Casey doesn't like that. While Casey is sneakier than she portrays herself to be, her "good person" side will come out if she really believes Derek needs her help, whether he really needs help, such as in the episode "Grade-Point: Average", or he's pretending to get his own way, such as in the episode "The Party", or somewhere in between, such as in the episode "The Wedding",. In the episode "Prank Wars", Casey is very concerned for Derek and fights against the principal for him not to be expelled. But Derek also cares about Casey, as shown in the episode "Crushing the Coach." where Derek goes out of his way to prove to Casey that her new boyfriend is a jerk. At times, Derek can be a true friend to Casey, and save her from dangerous situations.
Casey uses Lizzie in much the same way that Derek uses Edwin, but Lizzie's much more loyal than Edwin. When Casey wants Lizzie to do something unethical or "mean" to beat Derek, she has to badger her into it. While the sisters have very different interests, they share a general appreciation for organization and femininity, although Lizzie isn't as passionate about it as Casey would like. They are very close.
Although Casey loves Lizzie, they are the opposite of each other. Casey is some-what girly and doesn't enjoy sports, Lizzie is tomboy-ish and enjoys sports, like soccer and hockey. And to Casey's dismay, Lizzie likes Derek and kind of enjoys living with the Venturis, although when Casey's around, she pretends to hate it. Even though Casey controls Lizzie like Derek controls Edwin, she is rarely mean and never violent. Lizzie admits herself that Casey is "usually a great sister." Lizzie has brown hair that goes down to her shoulder. She is environmentally friendly and has a love for animals and the environment.
Casey has mixed feelings about Marti - on one hand, she's a cute little kid, the most tolerable of the Venturis in Casey's eyes, and she really likes Casey. On the other hand, she's a Venturi, and a weak one at that, making her the quickest possible route to the takedown of Derek. Casey is always an excellent babysitter for Marti - she feels a little sorry for Marti since she grew up in a house of guys. Casey and Marti have a good relationship. Marti seems spoiled and Edwins says she uses " Special Powers" to get what she want. She uses super cuteness.
Marti is portrayed as cute, funny and energetic. In the first season, her brown hair is short down to her neck. In later seasons, her hair has grown to a back length.
As seen in the episode "House of Games" Marti didn't like Casey because she stepped on her imaginary friend Daphne, and quote, "Too late she hates you". Marti later forgives Casey though and loves her like a big sister. Through-out the series Marti starts to act older. Even though she is young, she still tries to prove to Casey she is smarter than what she seems at times.