Amadeus Ross [Nick Nolte] is a retired veterinarian who battles Alzheimer's disease. The eulogy at his wife Margaret's funeral starkly reveals how far his memory has faded. Three months later, his son Nick [Matt Dillon] and his granddaughter Matilda “Tilda” visit in Connecticut and realize he can no longer live alone. Nick persuades Amadeus to move to his home in England.
Nick is married to Sarah [Emily Mortimer], but their relationship is strained by past infidelities—one during their time in the US and another with her boss in the UK. Amadeus's presence stirs tension in the household, such as when he accidentally starts a kitchen fire while trying to bake a cake, which Sarah douses just in time.
As his condition worsens, Amadeus goes to see Eric Roberts as Dr. Holst, and struggles to answer even simple questions. Later, during a summer garden party, a fireworks mishap triggered by his confusion prompts Sarah to move out for a while.
Nick consults Dr. Holst again, who warns that moving Amadeus to a retirement home may be inevitable. Yet Tilda resists this path and, after Sarah returns, urges a different plan: the grandfather-and-granddaughter duo embark on a journey to Venice—the place where he and Margaret had spent their honeymoon. A pediatrician, Dr. Edwards, notes that visiting familiar places can help a person living with dementia.
They begin their journey by car, but Amadeus's confusion leads to a series of mishaps, including crashes from misreading one-way streets and red lights. When they attempt the London-Venice Express by train, Amadeus wanders off on the northern Italian leg, forcing a dramatic stop to the ride. The pair hide in a toilet stall while authorities search for them. A kind janitor named Mickey helps them continue toward Venice, and they eventually find shelter in a nunnery. The Mother Superior is moved by their story and arranges for a smoother path to Venice.
Back in England, Nick and Sarah follow them to Venice and check into the same hotel, though they do not recognize one another at first. Amadeus slips out during the night, and the next morning Tilda finds him seated on a bench by the sea—the bench where he once sat with Margaret during their honeymoon. By this point, Amadeus no longer recognises his granddaughter. Nick and Sarah reunite, and the family decides to slow their lives to care for him, hiring a carer to help at home.
As Amadeus moves into a nursing home, Emily Cox the Nursing Home Manager helps coordinate his care. The Venice journey helps heal Nick and Sarah’s relationship, and nine months later Sarah gives birth to a son named after his grandfather. In his final days, Amadeus finds peace, dying quietly in bed with Tilda by his side. At the funeral, Tilda lies on the grass looking up at the sky, keeping the promise that her grandfather would watch over her from heaven.
