Sheila has agoraphobia, which she developed sometime during Karen's childhood. Due to her agoraphobia, Sheila has a fear of the outside world and is unable to leave the house. She has a rocky marriage with Eddie Jackson, who is overbearing, clown-obsessed and very religious; Eddie is unsupportive of Sheila's agoraphobia, dismissing it as a “made-up disease for people who want to sit on their ass at home and watch TV.” As a result of Eddie’s neglectfulness, Karen looks after Sheila and takes care of her medications; she also stands up to her father, who is cruel and makes jokes about Sheila’s phobias. Sheila takes pleasure in sexual activities and taking control, something in which Eddie and Frank find no pleasure.
Sheila is introduced in the pilot episode as the mother of Lip's girlfriend Karen. Eddie discovers Karen performing oral sex on Lip’s brother Ian. Angered and disgusted, Eddie packs his bags and moves out, upsetting Sheila.
Lip’s alcoholic father Frank Gallagher finds out about Eddie’s departure. Frank, who has been searching for a new home, ventures over to Sheila’s and attempts to manipulate her into allowing him to stay in her house. Sheila gladly invites Frank into her home and lets him move in. Now officially living in the Jackson house, Frank freeloads and takes advantage of Sheila’s disability checks, to Karen’s dismay. In Casey Casden, Eddie ultimately moves back into the house, explaining that he can’t live somewhere else and continue to support Sheila and Karen. Sheila begins to act coldly towards Eddie, still upset by his previous actions.
In Frank Gallagher: Loving Husband, Devoted Father, Sheila is asked to babysit Frank’s youngest son, Liam. The babysitting initially goes well until Liam ventures off outside and into the front yard while Sheila isn't looking. Sheila is terrified of leaving the house to save Liam; however, acknowledging that Liam could potentially get into danger, Sheila musters enough courage to briefly go outside and retrieve Liam from the front yard. Sheila is visibly proud by her brief accomplishment.
In Nana Gallagher Had an Affair, Sheila is thrilled when Eddie attempts to reconcile his relationship with Karen through a purity ball, a Christian father/daughter event where girls pledge their chastity. However, during the purity ball, Eddie angrily calls Karen a whore when she admits her extensive sexual history at the ball, as required by the ball’s program. Karen returns home and breaks down in front of Sheila, telling her what happened. When Eddie returns to the house, Sheila yells at him and kicks him out of the house, overcoming her agoraphobia in the process. Shortly after, Frank returns and acknowledges that Sheila is outside; surprised and overjoyed, Sheila proudly exclaims that she’s left the house.
In the season finale, Eddie commits suicide by jumping in the frozen lake; his death is unknown to Sheila, Karen and Frank.
At the beginning of the season, Sheila continues to make significant progress in overcoming her agoraphobia. She goes outside every day, and eventually announces her plans to walk to the Alibi Room. This worries Frank, who fears that Sheila will find out about his reputation and discover how awful he really is. Frank is ultimately saved when an airplane wheel randomly falls from the sky and hits the ground directly in front of Sheila; this causes Sheila to relapse, undoing all her hard work in overcoming her agoraphobia. Shaken by the airplane wheel incident, Sheila is unable to leave the bedroom, and she becomes further depressed when the police find Eddie’s dead body floating in the lake. Upon learning of Eddie’s death, Frank pesters Sheila into letting him be in charge of Eddie’s insurance money. In Father’s Day, Frank is arrested over Karen’s Daddyz Girl video; Karen has Frank released when she tells the police that she was in the instigator. When Frank returns home, Sheila tearfully apologizes to Frank over Karen’s actions.
In Can I Have a Mother, Frank’s mother, Peggy, visits the Jackson house; Sheila is put off by Peggy’s rude nature, and when Peggy calls Sheila a “nut job”, Sheila orders her to leave. When Karen and Jody throw a wedding party in the Jackson house, Peggy crashes the party, to Sheila’s dismay. Overwhelmed by Peggy’s appearance and uncomfortable with the amount of people in the house, Sheila gets drunk, mixing her medication with alcohol. She eventually returns to the party and gives a drunken toast, in which she questions the father of Karen’s baby, reveals the details of her sex life with Eddie, and describes the Gallagher family as “the ones in that house where the cops always came.” Things turn awry when Sheila and Peggy get into an argument, which escalates with Peggy pulling out a gun and pointing it at Sheila’s face, causing everyone to panic. Jody and Karen come between the women, and the gun is pulled from Peggy; a shot gets fired into the smoke detector, abruptly ending the wedding party.
The day after the wedding party, Eddie’s insurance check arrives. Frank discovers that Eddie changed his beneficiary, leaving the money to Karen instead. Sheila witnesses Frank, who is angered over the news, verbally attacking Jody. Now seeing the real Frank, Sheila kicks him out of the house. In Parenthood, Peggy becomes very sick, forcing Frank to move her out of the Gallagher house and back to Sheila’s home. Peggy and Sheila make amends, apologizing for their fight, and Sheila and Jody care for Peggy during her final days. Wanting to hasten her own death, Peggy asks Sheila to end her suffering by suffocating her. Although initially reluctant to commit murder, Sheila is persuaded when Peggy gives her permission. Sheila and Peggy say goodbye to each other, and Peggy passes away after Sheila smothers her with a pillow.
In the second half of the season, Karen dumps Jody and violently throws him out; however, Jody continues spending time in the Jackson household and bonds with Sheila. In Hurricane Monica, Sheila apologizes to Jody for Karen’s behavior, and exclaims that Jody is a “good man”; the two unexpectedly have sex. Unbeknownst to Sheila and Jody, Karen discovers the two having sex. Karen later informs Sheila that she knows about her affair with Jody, but states that she’s okay with the relationship, as it gets Jody off her back.
In the penultimate episode, Just Like The Pilgrims Intended, Sheila overcomes her agoraphobia from excitement when Karen gives birth. The baby boy has Down Syndrome and is of Asian-American descent; Karen reveals that the father is probably a classmate, Timmy Wong, and expresses her disdain for the baby, refusing to even hold the child. When the adoptive parents that Karen initially chose don’t want the baby because of his disability, Sheila and Jody abduct the baby from the hospital to ensure he has a better future, rather than staying in the foster care system. In the season finale, Karen returns home and implores Sheila to return the baby to the hospital. When Sheila refuses, Karen gives her an ultimatum: either the baby goes or Karen does. Sheila pleads with Karen, but is unable to change Karen’s mind; Sheila ultimately decides to keep the child, spurring Karen to pack her bags and run away.
At the beginning of the season, Sheila and Jody struggle with parental life. Distraught by Hymie’s constant crying, Sheila invites Frank to move in with them, as Frank is the only one who can successfully calm Hymie down. Sheila has begun getting bored with her sex life with Jody, and she confides to Frank for advice to get Jody to use her fetish toys; Frank reluctantly agrees to be Jody’s sex coach. The plan backfires, with Jody ultimately relapsing in his sex addiction, spurring Sheila and Frank to start an intervention.
In Cascading Failures, the Gallagher children are taken away by Child Protective Services following a surprise CPS visit. Sheila plays a crucial role in getting the kids back into Fiona’s care by posing as Frank’s ex-wife Monica for the petition.
In A Long Way From Home, Sheila gets a visit from Timmy Wong and his mother, who want Hymie to live with them. Sheila is initially resistant; however, with Jody having relapsed, Sheila realizes that her home is unfit for a baby, and she decides to give Hymie back to his biological family. The next day, Karen suddenly returns home. Sheila is overjoyed by Karen’s return, and the two embrace; Karen apologizes to Sheila for the ultimatum, and expresses interest in Hymie, implying that she came back for her child. However, after speaking with Timmy Wong’s mother, Sheila discovers that Karen had previously contacted the Wongs and told them to take Hymie away from Sheila. Sheila confronts Karen, who states that she called the Wongs because she wanted to return to a simpler time before Hymie.
Feeling betrayed by her daughter, Sheila becomes depressed and refuses to communicate with Karen. Debbie visits Sheila and, seeing that she's depressed, decides to skip school to spend the day with her. Sheila confides in Debbie about Karen, but after Debbie gives her a pep-talk that lifts her spirits, Sheila ultimately decides that she needs to reconcile with her daughter. Later that night, Sheila gives a heartfelt apology to Karen. She apologizes for her previous mental health issues, and acknowledges that she couldn’t be there for Karen because of her agoraphobia. Her attempt to reconnect nearly works; the two share tears, but before Karen can respond, she receives a text message supposedly from Lip, asking her to meet him at the park. Karen leaves the house to walk to the park; while crossing the street, Karen is violently rammed by a speeding car. She is flipped completely on top of the car, and is left on the road, unconscious, as the car speeds away.
Karen is put into a coma following the hit-and-run, and Sheila and Jody stay in her hospital room to comfort Karen. Sheila decides to break up with Jody, expressing that Jody is Karen’s prince, and she took Jody away from her daughter. After Karen awakens from her coma, Sheila notes Karen’s drastic personality change; the doctor notes that Karen is unable to form new memories, only being able to recall memories from before the accident. In the season finale, Sheila says goodbye to Jody, who is taking Karen and Hymie to Arizona in hopes of giving Karen a better recovery. Before Jody drives away, Sheila tearfully says goodbye to Karen, expressing “I know I have to let you go.” Later that night, Sheila goes to the Gallagher’s house to celebrate Lip’s graduation. During the party, Sheila shares a special moment with Debbie, who suggests that Sheila find friends her own age. Inspired by Debbie’s advice, Sheila starts doing group sessions for women looking to buy sexual products.
At the beginning of the season, Sheila struggles to cope with the fact that she’s alone. She spends a lot of time at the Gallagher house, voluntarily cleaning and looking after the kids while Fiona is away.
Sheila starts to experiment with online dating, and she begins dating Roger Running Tree, a Native American cowboy taking care of his junkie sister’s five children. Roger Running Tree and the kids briefly move in with Sheila during their short stay in Chicago. Sheila quickly forms a close bond with the kids, but she is forced to say goodbye when they have to leave for their reservation. Experiencing an empty nest once again, Sheila packs her bags and decides to join Roger Running Tree’s family at their reservation. During Sheila’s absence, Frank and Sammi, who have been kicked out of the Gallagher house by Lip, break into Sheila’s house. In an attempt to raise money for Frank’s liver transplant, Sammi raises money by selling Sheila’s furniture and putting Sheila’s house up for sale.
In The Legend of Bonnie and Carl, Sheila returns from the reservation and discovers her house empty, as Sammi had sold most of the furniture. Sheila also finds Frank in deteriorating health. Sheila reveals to Frank that Roger Running Tree had anger issues; however, Sheila continued to form a close bond with the children, and announces her plans to adopt Roger Running Tree’s kids. In order to legally do so, Sheila must be married, so she tricks an incapacitated Frank into marrying her while he is in the hospital.
Frank wakes up from his liver transplant surgery and discovers his marriage to Sheila. Now married to Frank, Sheila is eligible to adopt the kids; however, her request for adoption is denied, and the children must live with their great-grandfather.
Frank and Sheila are now living together, while Sammi lives in her trailer next door. Sheila shows a dislike for Sammi, who has started to act out, such as openly having sex in Sheila's house. Sheila cares for Frank, making sure he’s taking his medications. While Frank works on his "Milk of the Gods" beer in the basement, Sheila contemplates an offer made by two women who would like to purchase her house for double the market value. Sheila wants to accept the offer and use the money to travel the world, but Frank disagrees.
Frank tries several times to convince Sheila to stay, asking her to keep her house so it can be "their nest". He blames his post-transplant weakness and desire to renew his and Sheila's vows for his resistance to selling. Sheila eventually caves, deciding to cancel her plans and stay with Frank. Sammi suddenly enters the house uninvited and argues with Frank; Frank, who is still working on his beer still, had promised a man sex with Sammi in exchange for brewery equipment. When Sammi attacks Frank, Sheila intervenes, and the fight eventually resorts to outside the house. Having had enough, Frank blows up at both girls. He angrily insults Sheila, calling her a "lumpy smothering pervert" and "certified whack-job." He criticizes Sheila for her previous mental health issues, her sexual desires, her relationship with Jody, and her "unreasonable complicated cooking." Immediately following Frank's tirade, Sheila's house blows up, due to Frank's beer production brewing in the basement.
The RV that Sheila had bought earlier pulls up in front of the blown-up house. Ignoring the flames and the burning contents of her home, Sheila walks past Frank and hops into the RV. Frank makes one last-ditch attempt to get Sheila to stay, but Sheila drives past him, speeding down the Chicago road, finally fulfilling her dream of seeing the world.