The following version of this book was used to create the guide: Weiner, Jennifer. Mrs. Everything. Simon and Schuster, 2019.

This novel spans five decades in the lives of Jo (the protagonist) and Bethie Kauffman. Jo and Bethie's lives are influenced by the sociocultural, sociopolitical, and socioeconomic progress of the women's movement that spans their lives. As relatively socioeconomically privileged white women, Jo and Bethie are members of the minority group most likely to benefit from the increasing personal and professional autonomy made possible by the women's movement. Though Jo and Bethie experience many of the same events, the use of an omniscient narrator ensures that neither sister's perspective is privileged. Jo's death from terminal breast cancer is foreshadowed in the prologue of the novel. This foreshadowing reveals that how the events in the plot of the novel shape the women Jo and Bethie become is more important than the events themselves.

Jo and Bethie have contrasting relationships with feminine gender roles. Jo, a closeted homosexual, longs to be a professional writer who shares her life with a woman. She rejects the feminine gender norms of her generation, by which a woman is only defined as a (heterosexual) wife and mother. Bethie, by contrast, enjoys emulating the feminine ideal: beautiful, charming, and graceful. If Bethie does not articulate her professional and personal goals as clearly as Jo does, it is only because a woman of her generation who embodied feminine gender norms was not expected to have personal aspirations. At the beginning of the novel, Jo resists feminine gender norms and Bethie embraces them. As each woman's relationship to her body changes, her relationship to feminine gender norms changes as well. After Jo's college girlfriend breaks up with her because she does not have the courage to openly live with a woman, Jo's own resolve to resist feminine gender norms weakens. She marries a man, hoping a heteronormative marriage will provide her with sociocultural influence and socioeconomic stability. She enjoys becoming a mother, but she is not fulfilled by her solely domestic role.

After Bethie endures multiple sexual assaults and an illegal abortion, she rejects feminine gender norms. She gains weight and takes drugs, trying to physically isolate herself from the body over which she believes she no longer has any personal autonomy. Eventually, she moves to Blue Hill Farm. She embraces feminist ideals, and sells homemade jam with the other members of the commune. Now it is Bethie, not Jo, who is taking advantage of the personal and professional autonomy the women's movement has made possible. She takes Jo to Blue Hill Farm, hoping time for self-reflection will help Jo find the courage to leave her husband and live openly as a homosexual woman. Instead, Jo resents Bethie's critique of her marriage. The sisters have a fight, the most serious fight of their relationship. Finally, Bethie admits she resents Jo, because she believes Jo should have rescued her from her first sexual assailant, their paternal uncle. After their father died suddenly and their grieving, overwrought mother found a full time job to support her family, Jo became a surrogate maternal figure for Bethie. When Jo could not immediately rescue her from her sexual assailant, she failed to live up to Bethie's expectations for someone fulfilling a maternal role. Eventually, the sisters forgive each other.

Jo never leaves her husband, but she is relieved when he leaves her to move in with a woman with whom he is having an affair. Before her marriage ended, Jo developed a fitness routine designed for anyone of any physical ability. She taught neighborhood classes and sold workout videos locally. After her divorce, Jo's husband, who had told her he did not think the idea was widely marketable, shoots a video of his new girlfriend doing Jo's fitness routine and markets it as though it were his own. Jo cannot afford to pay a lawyer to sue her husband for stealing her intellectual property. Bethie, who has left Blue Hill Farm and become a successful businesswoman by supplying restaurant chains with jam made using Blue Hill Farm's recipes and marketed with the Blue Hill Farm name, gives Jo the money to hire a lawyer. Jo wins a sizable settlement. Single, confident, and financially secure, Jo finds her college sweetheart. The two women still love each other. They move in together, much to the chagrin of her youngest daughter, who is still living at home when the couple first reunites. Both Jo and Bethe are filling sociocultural roles they find fulfilling. Jo is a financially independent woman and devoted mother who is openly living with the woman she has always loved. Bethie is a successful businesswoman whose husband supports her career and her decision not to have children. Like Jo, Bethie is strong and confident enough to disregard social norms, sustaining her husband even when their interracial marriage leaves them isolated.

After Jo and her wife have been together for ten years, Jo learns her breast cancer is no longer in remission. She has a terminal diagnosis, and she does not want to endure radiation and chemotherapy for a second time. She chooses an assisted suicide Bethie. promises Jo's wife and she will care for Jo at Blue Hill Farm, which Bethie still owns. She promises she will reunite the whole family, so Jo can be surrounded by people she loves. As Jo is dying, she sees Hillary Clinton's 2016 presidential campaign rally on television. Jo is confident Clinton will win the presidential election, though the reader knows she will lose to Donald J. Trump. In Jo's last vision, she has returned to her childhood home. Her parents are letting her wear pants and a shirt instead of a dress, even though, in truth, her mother always expected her to obey feminine gender norms. After Jo dies, Bethie takes Jo's children and grandchildren to her sister's and her childhood home.