Nancy believed Karen and Ted never truly loved each other, saying they only got married because she was young and Ted had a well-paying job. Karen herself appeared to be at least somewhat frustrated with her marriage.
After the disappearance of Will Byers, Karen told her children that they could not leave the house until he was found, forbidding Mike to search for Will and Nancy to go "study" at Barbara Holland's house.
On November 8, Karen allowed Mike to skip school, believing he was distraught over Will's disappearance, At the dinner table, Nancy lied that she was going to a special assembly at school to support Will and his family - this was a cover story so that she could hang out with Steve. After some reluctance, Karen gave her permission to go - as long as she was back by 10.
After Nancy returned from Steve's party, Karen furiously questioned why she was out so late. When Karen asked about the sweatshirt Nancy was wearing, she responded that she borrowed it from Steve. Karen tried to tell Nancy that she could trust her and talk about anything that happened, but Nancy brushed her off.
The next day, Karen visited Joyce Byers at her house along with her daughter Holly, gifting her a casserole. Karen noticed that the house was decorated with Christmas lights, and Joyce gave the excuse that she hung them for Will because he loved Christmas. Noticing Holly had walked off from the dinner table, she and Joyce found her in Will's room. Joyce thanked Karen for the casserole but insisted that they leave the house. Later, Nancy revealed to Karen she was worried about Barb's disappearance. Later that night, Mike returned home with the news that Will's body was found, crying in her arms.
Before leaving the next day, Karen asked Mike if he wanted to come with her to rent a movie, even an R-rated one. Mike declined for fear of leaving Eleven alone in his house. Karen went off on her own to check up on Barb's parents.
After being questioned by the police about Barb's disappearance, Karen insisted Nancy was lying to the police about talking with Steve in his bedroom. Nancy finally admitted to Karen that she slept with him.
Karen, Ted, Nancy, and Mike all attended Will's funeral.
Department of Energy agents arrived at the Wheeler house, looking for Eleven. When questioned, Karen answered that she did not know of any girls living in the house, and that if she had, she would know. She and Ted were eventually allowed to leave their house; they arrived at Hawkins Middle School in their car, reuniting with their son. They were present at the hospital, waiting for news on Will's status following his recovery.
On Christmas Eve, Jonathan picked up Will from another Dungeons & Dragons campaign at the Wheelers'. As they left, Karen exchanged festive greetings with them.
On October 29, 1984, Karen was seen in the kitchen with her husband and Holly, watching Nancy chase Mike for taking change from her piggy bank. On the next day, while eating at the dinner table, Ted and Karen tell Mike to put some of his toys in two boxes as punishment for taking some of Nancy's change.
Four days later, while eating breakfast with her family, Karen hears Nancy say she's planning to go have a sleepover at a friend's house for the weekend and asks if it's okay which Karen says yes (unaware that Nancy plans to expose the Hawkins Lab with Johnathan's help, in order to avenge Barbara's death).
On the next day, while Karen was on the phone, Ted answers the door, after hearing the doorbell rang, and meets Dustin who asks for Mike. Ted says Mike is over at Will's, but Dustin says he can't reach anybody at Will's so he asks for Nancy. When Ted asks Karen where Nancy is, she says Nancy's supposedly at Ally's, causing an irritated Dustin to leave. Later, while reading a erotic novel in her bubble bath, she answers the doorbell, after Ted had fallen asleep on his couch, and meets Billy. After flirting, she gives him the address to the Byers house and he leaves the house, with Karen sensually staring at his bottom.
A month later, Karen attended the funeral of Barbara Holland with Nancy and Ted. When Mike gets ready to go to the Snow Ball, Karen takes pictures of Mike, much to his annoyance as she keeps taking too many pictures of him.
At the Hawkins Community Pool, Karen Wheeler and several other mature women are waiting for Heather Holloway, the lifeguard on duty, to step down so that Billy Hargrove can come forward, each woman ogling him. Billy compliments Karen’s swimsuit, and later after watching her swim, compliments her again and tells her she has perfect "form". After some proding, Billy manages to convince her to come with him to Motel 6 for "swimming lessons", where it is "very private". That night, Karen beautifies herself and takes off her wedding ring, preparing to go to Billy, but notices her husband Ted Wheeler asleep with their daughter Holly Wheeler, and decides to be faithful instead.
The next morning Karen takes a call from El to her son Mike Wheeler, staying on the line and becoming shocked when Mike lies about his ’nana being gravely ill. Later, Karen returns to the Hawkins Community Pool and apologizes to Billy about standing him up the night before. Billy however, was not present either, and has been Flayed. He manages to control his unnatural urge to attack Karen, but only just, and instead tells Karen to stay away from him.
Karen’s daughter Nancy later returns home from being fired from The Hawkins Post, going to her room. She eventually comes out however, and confides in Karen her concerns that Jonathan Byers might be right, that she just insists on being right even if she isn’t. Karen supports Nancy, saying that the journalists at The Post are "shitheads", and encourages Nancy to finish her story, that she might get picked up by a national outlet and go right over The Post’s heads.
With Ted and Holly, Karen later goes to the Fun Fair and bribes the operator of a ferris wheel to stop the ride while she and her family are at its apex, enabling them to better view the Fourth of July fireworks. Holly however, is distracted by the trees moving seemingly of their own volition; signs of the Mind Flayer’s passage. Hopper and Joyce later find Karen on an amusement park ride, asking where the kids are, but Karen doesn’t know where exactly they are as she has trouble keeping track.
After her son Mike says goodbye to El and Will, Mike returns home when Karen is cooking, hugging her.
Shown to be a stereotypical overbearing mother, Karen is heavily concerned about the wellbeing of her two older children, Nancy and Mike, following the disappearance of Will Byers. She is dubious of Nancy upon discovering her relationship with Steve.
Her own relationship with Ted seems to be a loveless marriage as Ted is monotonous and one-note for the length of the most of the time.
- Ted Wheeler – Husband. Ted and Karen are married in a loveless marriage. They seem to argue frequently.
- Nancy Wheeler – Daughter. Karen cares very much about Nancy but they can get mad at each other especially when Karen finds out Nancy slept with Steve.
- Mike Wheeler – Son. Karen cares about Mike and is seen comforting him after Will's "body" is found. She also is worried for Mike when the government agents arrive looking for him.
- Holly Wheeler – Daughter. Like with Nancy and Mike, Karen cares very much about Holly.
- Billy Hargrove – Karen meets Billy when he is in search of Max. The two flirt together before Karen gives him the address. It's unknown if Billy was simply manipulating Karen or really flirting with her but Karen does seem attracted to him, sexually staring at his booty when he leaves the house.
|Season One appearances|
|The Vanishing of Will Byers||The Weirdo on Maple Street||Holly, Jolly||The Body|
|The Flea and the Acrobat||The Monster||The Bathtub||The Upside Down|
|Season Two appearances|
|MADMAX||Trick or Treat, Freak||The Pollywog|
|Will the Wise||Dig Dug||The Spy*|
| || ||The Gate|
|Season Three appearances|
|Suzie, Do You Copy?||The Mall Rats|| ||The Sauna Test|
|The Flayed*|| ||The Bite||The Battle of Starcourt|
|Nancy Wheeler||Mike Wheeler||Holly Wheeler|
- "I hope you're enjoying your chicken, Ted."
- "I want you to feel like you can talk to me."
- "You are not crazy."
- Karen has met most of the main characters, apart from Max, Bob, Dr. Owens, Robin and Erica.