Set during World War II, the novel opens in June 1944 with Tess DeMello Kraft narrating a car accident that kills her sister-in-law, Lucy Kraft. Tess drives the family's old Buick at Lucy's insistence to deliver headstone money to Adora, a former family maid in the Black neighborhood of Ridgeview whose grandson died of polio. A tire blows out near a river, sending the car into the water. Tess escapes, but Lucy's legs are pinned beneath the dashboard, and she drowns.
The story flashes back to August 1943 in Baltimore's Little Italy. Tess DeMello, a twenty-three-year-old nursing student, is engaged to Vincent Russo, a newly minted doctor whose family lives next door. They have been together since Tess was fifteen and have never been intimate. When Vincent leaves to volunteer with a polio epidemic in Chicago, his absence stretches from weeks into months as he takes a paying job and repeatedly postpones coming home.
At her best friend Gina Farinola's urging, Tess travels to Washington, D.C., for a weekend. At Gina's aunt's tourist home, they meet Henry Kraft, a quiet furniture factory owner from Hickory, North Carolina, who is missing three fingers on his left hand. Over dinner, Tess drinks far more than she ever has. Back at the tourist home, too intoxicated to think clearly, she has sex with Henry, her first time. She wakes filled with guilt.
Tess discovers she is pregnant. She considers sleeping with Vincent during his brief Christmas visit to pass the baby off as his but cannot compound the lie. Gina arranges an illegal abortion, but at the last moment Tess visualizes her baby and refuses. She travels to Hickory to ask Henry for financial support. Henry surprises her by proposing marriage, saying he wants to give the child his name. Tess accepts.
She tells her mother, who guesses the pregnancy and throws her out. Days later, Vincent calls: Tess's mother has been found dead from a fall caused by a seizure or stroke. Consumed by guilt, Tess writes Vincent a letter claiming she fell in love with someone else, leaves it with her engagement ring, and departs for Hickory.
Tess and Henry marry before a justice of the peace. On their wedding night, Henry does not touch her, a pattern that persists. She moves into the Kraft family home, where Henry's mother, Ruth, is politely hostile and his sister Lucy is openly contemptuous. Ruth insists Tess abandon Catholicism, calls her a gold digger, and discourages her from nursing. Henry is affectionate only in public.
Tess befriends the family's maid, Hattie, who directs her to Reverend Sam, an elderly Black man in Ridgeview who communicates with the dead. Reverend Sam channels Tess's mother and relays her request to "finish the book," a reference to
A Tree Grows in Brooklyn. Tess begins visiting him regularly, finding him the kindest person in Hickory.
Tess secretly applies for her registered nursing exam. Henry initially forbids it but then drives her himself. She passes. Shortly after, at five months pregnant, she delivers a stillborn boy she names Andrew. Henry refuses to acknowledge the loss. While hanging clothes in Henry's armoire, Tess discovers a false bottom concealing bundled cash. When she raises the possibility of annulment, Henry has sex with her that night for the first time, and Tess believes he is locking her into the marriage.
The polio epidemic worsens, and Lucy dies in the river accident described in the prologue. Tess is excluded from the funeral. Ruth calls her "common" and says Tess destroyed both her children. The household tensions become unbearable, and Tess moves out to live with Grace Wilding, a nurse she has befriended.
At a community meeting, county health officer Dr. Whims announces the conversion of a lakeside camp into a polio hospital, to be built in fifty-four hours. Tess wants to nurse there, but Henry and Ruth forbid it. Reverend Sam tells Tess a spirit guide named Walter insists she must help. When a panicked couple brings a boy to the construction site believing he has polio, Tess calmly determines his symptoms are harmless. Henry witnesses her competence and relents.
Tess throws herself into the work, caring for paralyzed children, applying hot wool packs using the Sister Kenny method, and training on the iron lung, a steel respirator for patients whose chest muscles are paralyzed. Honor, Adora's daughter, brings her four-year-old daughter Jilly to the hospital with polio, and Tess is assigned as Jilly's nurse. Tess helps Honor see Jilly through the ward windows, and the two women begin to connect.
A new doctor arrives, and Tess recognizes Vincent's brown eyes above his surgical mask. After their shift, she confesses everything. Vincent is angry, not about the sex, but that she did not trust him. He reveals he was not celibate before their relationship and says he would have forgiven her.
When Amy Pryor, the mayor's pregnant daughter, is placed in the iron lung with severe paralysis, Tess becomes her primary nurse. One morning, she discovers Amy's premature baby crowning, delivers the infant alone, and performs mouth-to-mouth resuscitation when he does not breathe, reviving him. The story makes front-page news. Vincent publicly credits Tess and Grace for saving both lives, and Ruth adds the newspaper clippings to her family scrapbook, a sign of grudging acceptance.
One night, Tess stops at the factory and finds Henry in bed with Honor. Henry confesses that he has loved Honor since they were teenagers. Butchie and Jilly are his biological children. Butchie's real name was Walter, the spirit Reverend Sam channeled. Henry reveals he married Tess partly to give her baby a name but also as cover for his forbidden relationship with Honor. The cash in the armoire comes from selling counterfeit gasoline rationing coupons printed at the factory, with Lucy serving as courier. Tess demands a divorce, and Henry asks for a month.
Vincent tells Tess that since she married before a justice of the peace, the Catholic Church does not recognize the marriage. They plan to marry and return to Baltimore.
A fire destroys the factory. Charred remains are identified by a left hand bearing only a thumb and forefinger. Tess mourns, but when she opens the armoire, the money is gone, replaced by an envelope containing cash, gas coupons, and three skeletal fingers from Reverend Sam's stolen skeleton. Henry has faked his death. Zeke, Henry's old friend, confirms Henry is heading to Washington State, where interracial marriage is legal, and asks Tess to drive Honor and Jilly across the country using the Green Book, a guide to safe lodgings for Black travelers.
In March 1945, Tess and Vincent pick up Honor and Jilly. They plan to deliver the pair to Henry, then return to Baltimore to open a pediatric practice and marry.
An epilogue set in April 1955 shows Tess in medical school, living in Baltimore with Vincent and their eight-year-old son, Philip. Church bells ring: The Salk polio vaccine has been approved. A postcard arrives from Mexico City, signed with initials representing Henry, Honor, Jilly, and three additional children. Vincent asks Tess if she has ever considered how she changed Hickory. The novel closes with Tess recognizing the scope of her own impact.