In "Gnomes", it is revealed that the Tweaks are the joint owners of Tweek Bros. Coffeehouse family coffee shop, which only stays open due to being the only coffee shop in town. However, when Harbucks (a parody of Starbucks) plans to open a shop in South Park, Richard grows concerned that they'll be run out of business.
Upon discovering that their son Tweek and the Boys need to write a current event report in front of the Town Council (in order to prove to them that Mr. Garrison is a competent teacher), Mr. Tweak decides to use the boys to push his agenda regarding Harbucks. He proceeds to write a long-winded paper about how big business is destroying small family-owned business. The speech works, causing the town to turn against Harbucks and try to push through a legal proposition to outlaw Harbucks.
While Richard is thrilled at having used the kids to push his beliefs, Mrs. Tweak is disgusted by her husband's behavior, wanting nothing more to do with it. When the boys later discover from the Underpants Gnomes that big corporations are good, she joins the boys and explains to the town that Harbucks got to where it was by being the best. Richard, realizing she is right, makes amends with the owner of Harbucks, who asks him to run the South Park branch.
When they next appear in "Tweek vs. Craig", Richard tells Tweek that when he was in high school, all the young men were after Mrs. Tweak, but she only had eyes for Richard. One day, a football player who went by the name "Quib" wanted her, and he challenged Richard to a fight. Richard doesn't say what happened after that, other than that Quib moved away. In "Cartman Joins NAMBLA" She Was With The Women Reunited With Their Sons At The South Park Inn. Mrs Tweek also has a cameo appearance in the episode "Towelie" as the second victim of the towel massacre, the gunmen get her as she is hanging up her laundry.
Her next major appearance was in "South Park is Gay!", in which the men and boys of South Park begin obsessing over the new Metrosexuality fad caused by Queer Eye for the Straight Guy. At first Mrs. Tweak and the rest of the wives love the new versions of their husbands and sons, but soon realize that its not as good as they initially thought. When the men and boys become too wimpy and shallow, the wives realize that they preferred their husbands been strong men. The wives then proceed to go to New York, where they then kill the Queer Eye guys, who are revealed to be Crab People.
Mrs. Tweak wears an ankle-length turquoise dress with a white apron. Her hair is shoulder-length, straight, and light brown. She talks calmly. She seems to be more rational than her husband.
They have a son, whom they have named after the family name. Unlike either of his parents, Tweek has sunny blond hair. This could mean that he is a throwback to an older ancestor or blond is a recessive gene in both parents.
Tweek alleges that his parents "never help" in "Tweek vs. Craig", and bangs his head into the table, with his parents not noticing.
In "Child Abduction is Not Funny" it is shown that despite sometimes using abusive methods towards their son for his own safety, they care deeply for him like any normal parents and are only trying to protect him.
- "Gnomes" - Debut Appearance. Comments on her her husband writing their son and The Boys' report about corporate take overs.
- "Tweek vs. Craig" - Her husband explains to their son that all young men were after her as a teenager.
- "Cherokee Hair Tampons" - Says that Kyle Broflovski looks terrible when his kidneys fail.
- "Towelie" (cameo) - Seen when the army shoots down her towels.
- "South Park is Gay!" - At first, she thrilled about the metrosexual fad, but later starts to feel annoyed with it.
- "Child Abduction is Not Funny" - Attempts to prevent her son from being abducted.
- "It's Christmas in Canada"- Seen in the crowd of people at the Christmas tree lighting in South Park.
- "Mystery of the Urinal Deuce"
- "201" - Seen with her family, when the coffee shop is being destroyed.
- "Sarcastaball" - Seen at the PTA meeting with all the other parents.
- "Informative Murder Porn" - Complains to the local cable company after her murder porn television programming is blocked and learns to play MINECRAFT.
- "Stunning and Brave" - Seen when PC Principal is announced as the new principal.
- "Tweek x Craig" - Proud of her son's "homosexuality", she is later distraught when Craig and Tweak break up.
- "Naughty Ninjas" - Seen in the protest against the police.
- "PC Principal Final Justice" - Seen at the gun show.
- "Skank Hunt" - Seen at the school assembly.
- "Not Funny" - Seen at Mr. Slave's Residence.
- "The End of Serialization as We Know It" - Seen in the crowd.
- "Franchise Prequel" - Asks Mark Zuckerberg to leave the Tweak Residence as he goes through their refrigerator.
- "Dead Kids"- Seen when Sharon calls the other parents together to speak about school shootings. Later seen when Randy sings.
- "The Scoots" - Seen in the Park County Community Center meeting.
- "Nobody Got Cereal? - Seen in front of Park County Courthouse, waiting for Stan's verdict on the negotiation with ManBearPig.
- "Unfulfilled" - Gets a new job at the Amazon Fulfillment Center, due to Tweek Bros. Coffeehouse's negative incomes.