Set in the late 1970s, the novel follows Ave Maria Mulligan, a 35-year-old self-described spinster who runs Mulligan's Mutual Pharmacy in the small coal-mining town of Big Stone Gap in southwestern Virginia. Ave is practical and self-reliant, filling prescriptions, volunteering as chief of the local Rescue Squad, and directing the town's summer Outdoor Drama. Her closest companions include Iva Lou Wade, the flirtatious Bookmobile driver, and Theodore Tipton, the high school band and choral director originally from Scranton, Pennsylvania. Ave's mother, Fiametta, an Italian immigrant, died of breast cancer on August 2, 1978, and Ave is still quietly grieving. Her father, Fred Mulligan, died years earlier, a cold and emotionally distant man whose behavior Ave never understood.
One month after Fiametta's death, Ave visits Lew Eisenberg, a local lawyer, to settle her mother's estate. Lew gives Ave a sealed letter from Fiametta revealing that Fred Mulligan was not Ave's biological father. As a 17-year-old seamstress in Bergamo, Italy, Fiametta fell in love with a young man named Mario Barbari from the mountain town of Schilpario. She became pregnant and fled alone to Lake Maggiore, where a kind stranger named Ave Maria Albricci helped her board a ship to America. Fiametta named her daughter after this woman. In Virginia, Fred Mulligan married Fiametta knowing about her condition but never treated Ave as his own. The letter includes a photograph of the young Mario, inscribed "Ti Amo, Mario." Ave is devastated.
As the secret spreads through town, Ave's daily life continues. Jack MacChesney is a quiet coal miner from Cracker's Neck Holler. On closing night of the Outdoor Drama,
The Trail of the Lonesome Pine, Jack's girlfriend, Sweet Sue Tinsley, pushes him into a public near-proposal onstage, leaving Ave painfully aware of her unmarried status. Theodore rescues the moment by kissing Ave passionately in front of the crowd. When she tries to initiate a physical relationship that evening, Theodore gently refuses, explaining that they love each other as friends but are not in love. Ave is hurt but accepts his reasoning.
At the Pharmacy, Ave hires Pearl Grimes, a 15-year-old mountain girl from the impoverished Insko housing development who endures bullying from popular girls at school. Pearl proves smart and capable. It is Pearl who asks the pivotal question: "You gonna find your real father?" Ave resolves to search for Mario Barbari and enlists Iva Lou's help.
Ave's Aunt Alice Lambert, Fred Mulligan's sister, learns that Ave is not blood-related and demands a share of the Mulligan estate, asserting that Ave has no legal right to the property. To protect the business, Ave works with Lew to sell the Pharmacy to Pearl for one dollar, placing it beyond the Lamberts' reach.
The town buzzes with excitement when Elizabeth Taylor and her husband, Republican Senate candidate John Warner, visit Big Stone Gap in late October 1978. Theodore creates a spectacular halftime show for the football game featuring themes from Taylor's films. The next evening, at a library fund-raising dinner, Taylor chokes on a chicken bone. Ave and the Rescue Squad rush her to Saint Agnes Hospital, where a doctor dislodges the bone. The incident becomes the town's most famous story.
Tragedy strikes when Reverend Elmo Gaspar, the beloved local snake-handling preacher, is bitten by a rattlesnake during a revival and dies. Separately, Ave receives a letter from her mother's twin sister, Zia Meoli, in Italy, confirming that Mario Barbari is alive, still mayor of Schilpario, and unmarried. Ave writes to him but receives no reply.
One evening, Jack Mac visits Ave with apple butter from his mother, Mrs. Mac, and proposes marriage in a blunt, practical manner, citing their ages and his steady job. Ave is offended by what she perceives as pity and rejects him. Theodore later proposes as well, and Ave declines, explaining that she cannot trust any man until she understands her relationship with her father.
Exhausted by accumulated grief and stress, Ave collapses and sleeps for seven consecutive days in what the town calls the "Deep Sleep." Doc Daugherty diagnoses a nervous breakdown. When she wakes, she reflects on three lessons: She learned who her true friends are, she tends to bury problems until they overwhelm her, and she was not happy. In early March 1979, she receives a letter from Mario. He has no other children and no wife and asks her to write.
Iva Lou marries Lyle Makin, with Ave as maid of honor and Jack Mac as best man. At the reception, Jack gives Ave a copy of an out-of-print book about Schilpario that he special-ordered to help her find her father. They share a kiss, and Ave feels a deep connection, though she does not act on it.
Ave decides to leave Big Stone Gap permanently. She signs her house over to Pearl and appoints Iva Lou and Nellie Goodloe, the town's social planner, as Pearl's legal overseers until Pearl turns 18. She books a trip to Italy through Gala Nuccio, an Italian-American travel agent, and begins packing. Theodore, meanwhile, accepts a position as band director at the University of Tennessee. While delivering her mother's sewing materials to the MacChesney home, Ave finds Theodore and Jack entertaining Sarah Dunleavy, the new English teacher, and is stung by jealousy.
As Ave prepares to depart, Gala appears on her porch and reveals that the Italy trip was a fabrication designed to buy time for a surprise. Through the door walks Mario Barbari, followed by Ave's grandmother, her twin aunts, and her uncle. The entire reunion was arranged and funded by Jack MacChesney, who sold his new truck to pay for the family's travel. Ave approaches Jack to thank him, but he pulls away and walks off, still in love but believing she does not want him.
The family spends four joyful days in Big Stone Gap. Ave and Mario drive through the mountains, and he tells her he ended the romance with Fiametta because he already had a wife from an arranged marriage. Ave realizes her mother spent her life pining for a man she could never have.
After the family departs, Mrs. Mac confronts Ave directly, telling her that Jack is a man of quality and that Ave would be "the sorriest gal in the world" to let him go. She instructs Ave to be on the porch waiting when Jack comes home from work, then leaves to visit her sister. Ave drives to Cracker's Neck and waits. Jack arrives guarded and cold, but over supper, Ave breaks through his reserve. Jack reveals that he learned Italian from tapes, that he has loved her since sixth grade, and that Fiametta asked him years ago to look after Ave. They spend the night together. Ave describes the experience through a childhood memory of placing a fallen blue egg back in its nest: "I feel that I am safe and I am home."
The next morning, word arrives that Mrs. Mac has collapsed and been taken to the hospital. She tells Ave to take care of Jack, "because he took good care of me," then dies in her son's arms.
On April 28, 1979, Ave and Jack marry in a private Catholic ceremony. The town presents them with a jar of money for a honeymoon in Italy. They spend the summer with Ave's family. In Bergamo, Ave sleeps in her mother's childhood bedroom and discovers that the white walls and almond trim match the décor Fiametta replicated in Big Stone Gap. In Schilpario, Mario shows them a chapel with a stained-glass window depicting the Blessed Mother in a blue gown with gold stars and peacock feathers, exactly matching the description of Ave Maria Albricci, the woman who helped Fiametta board the ship to America. Ave and Jack have a second wedding at the chapel, with Mario giving her away.
Back home, Ave discovers that her airsickness was actually pregnancy. On April 28, 1980, their daughter, Fiametta Bluebell MacChesney, is born. They call her Etta, the name Mario used for Ave's mother. In the final scene, Ave watches Jack sitting on the porch with newborn Etta under the night sky: "a daughter learning to trust, and a father doing the thing he does best: protecting her."