In the picturesque town of Big Stone Gap, Virginia during the year 1978, we meet Ave Maria Mulligan - a spirited 40-year-old woman who fiercely embraces her independence. She operates the local pharmacy that she inherited from her deceased father, while her mother, an Italian immigrant, is celebrated as the town's beloved seamstress. Ave is not just a businesswoman; she immerses herself in community service activities, including delivering medications to residents in remote areas, volunteering for the Emergency Response Team, and passionately directing the annual production of Trail of the Lonesome Pine, inspired by John Fox Jr.'s renowned novel.
Ave's life takes an unforeseen twist when she makes a medication delivery to Nan McChesney, forming an unexpected friendship with her son Jack - a coal miner and one of her former classmates. Their brief encounter evokes a wave of nostalgia, prompting Ave to ponder their shared history. This reminiscence is cut short when Nan bluntly mentions that at 40, they are not too old to start a family, a remark that hangs in the air.
The tranquility of her life shatters when her friend Spec Broadwater, the town lawyer, brings devastating news about her mother's passing. During the graveside ceremony, Ave feels the sting of judgement from Fleeta Mullins - her outspoken friend and pharmacy co-worker - as she confronts her for placing a flower on her father's grave, revealing layers of complexity in their relationship.
Things intensify when Ave discovers a surprising revelation in her mother's will: a photograph of her biological father who resides in Italy. Her mother had journeyed to America while pregnant and married Fred Mulligan, Ave's late father, who never fully embraced her. This revelation sets Ave off on a transformative quest for self-understanding.
As the town's pharmacy becomes a focal point for change, Ave intervenes in a distressing situation where a group of affluent teens targets Pearl Grimes, a vulnerable Melungeon girl. By standing up for Pearl, Ave not only defends her but also offers her a job at the pharmacy, showcasing her commitment to her community.
After a lively cast party for the Lonesome Pine, Ave is surprised by Theodore's exuberant news that senatorial candidate John Warner is set to visit with Elizabeth Taylor, his wife. Events take a sticky turn when Theodore ends the night with an awkward kiss and a brusque farewell the following day.
Tragedy hits when a crisis at the local mine puts Jack’s life in jeopardy. Caught between her care for Jack and the tension building around him and Sweet Sue, Ave struggles with her emotions until she learns he is safe at the hospital. Their ride home feels charged with unspoken feelings as Jack’s affections seem to be shifting away from her.
Amidst the chaos, Ave finds an enchanting collection of old love letters between her mother and her real father, leading her best friend Iva Lou, the local librarian, to question her about her lack of romance. Simultaneously, Jack’s mother confronts him over his connection with Sweet Sue, whom she deeply disapproves of. Jack confesses his longing for the type of love his parents shared, but admits he doesn't truly love Sue; he only values her two young sons.
In a pivotal moment, Jack finds the courage to approach Ave for a moonlit walk, where he confesses that he has parted ways with Sweet Sue and reveals his long-standing crush on her. He suggests they marry, yet Ave feels aggrieved that he didn’t truly court her.
The chaos escalates further on the day of the John Warner Campaign visit when a mishap sends Ms. Taylor into a choking fit, leaving Ave in shock when she discovers that Jack has become engaged to Sweet Sue. Returning home, Ave faces her father’s aunt, Aunt Alice, who harshly criticizes her, threatening legal action to take control of the house and pharmacy.
In an emotional conversation, Theodore discloses that he received an offer for a band director position at the University of Tennessee, suggesting they part ways. In a moment of transparency, Ave shares family secrets with him, including her father's inclination towards men.
Amid mounting pressure, Jack's mother seeks Ave’s assistance against Sweet Sue's impending marriage to Jack. Overwhelmed, Ave spirals into a nervous breakdown, plunging into a deep sleep.
When days slip by in her absence, Iva Lou seeks the help of Pearl to reach out to Jack, urging him to help bring Ave back to herself, proposing that they are fated to be together. In a touching scene, Jack sneaks into Ave's bedroom, leaves a letter from her father, kisses her gently on the forehead, and quietly departs.
Upon waking, Ave uncovers a deep desire to find her father, driven by dreams of him. Spec advises her to distance herself from her possessions to ensure they are safe while she searches. In a surprising act of generosity, Ave sells the pharmacy to Pearl for just one dollar and gives Fleeta a significant raise, acknowledging her as a crucial part of her life.
As excitement bubbles in the community, Iva Lou eagerly announces her engagement to Lyle, asking Ave to be her Maid of Honor. In a hilariously chaotic ceremony, Ave and Jack become involved in attempting to keep the couple upright as their inebriation leads to comedic mayhem, while Aunt Alice and Uncle Wayne burst in with spite, demanding control of the family legacy. Yet, in a stunning twist, Ave surprises everyone by gifting the property to Pearl, which incites outrage from Aunt Alice, who spews bigotry towards Pearl, only to be met with disapproval from the townsfolk.
In the wake of these conflicted emotions, Sweet Sue drops a bombshell: she has reconciled with her estranged husband during Ave's hiatus. Jack lovingly presents Ave with a book about her father's hometown in the Italian Alps, serving as a tangible reminder of her lineage.
In a bold act of defiance, Ave leaves her Cadillac at Aunt Alice's doorstep, along with a note and the car keys, marking the end of a turbulent chapter. The story culminates in a rousing celebration at the Outdoor Theater, where friends come together to surprise Ave not only with the return of her father from Italy but also the arrival of her mother’s sister, Maria.
As the theater choir joins in harmony alongside Aunt Maria, Jack’s voiceover captures the essence of his and Ave’s enduring relationship, illustrating the joy and warmth they share with their two beloved children.
