Raimund Gregorius (Jeremy Irons) is a middle-aged teacher of classics in at a secondary school in Bern, Switzerland. One morning on the way to work, he sees a woman about to jump off a bridge. He pulls her down and takes her to the school. But this elusive young woman slips away, leaving behind her red coat and a book of philosophical musings by a Portuguese doctor named Amadeu de Prado.

Gregorius reads the book and is entranced by it. It works its way into his heart and his mind in so many vivid and surprising ways that he undergoes a transformation he can't explain. Inside the book is a ticket to Lisbon. Looking in the train station for the girl in the red coat, Gregorius impulsively leaps aboard the train, leaving behind his old life and stepping into a quest that stirs his soul.

In Lisbon, his intent is to speak to as many people as he can about Amadeu. He meets with the physician's sister Adriana (Charlotte Rampling); Father Bartholomeu (Christopher Lee) who recalls a speech he gave as a young man; a cranky old man Joao (Tom Courtenay) who worked with Amadeu in the Resistance movement in the 1970s against the authoritarian regime of Salazar; and two key players in the doctor's formative years as a revolutionary — Jorge (Bruno Ganz), and Estefania (Lena Olin).

Night Train to Lisbon by Pascal Mercier was a huge success — selling over two million books. This literary work has been adapted for the screen by Bille August (Jerusalem, Les Miserables, and A Song For Martin) who is a master in this genre.

In Lisbon, Gregorius meets Mariana (Martina Gedeck), a lovely and emotionally sensitive optician who gives him the encouragement he needs to carry on his quest. A quotation from Amadeu's book states: "We live only a small part of the life that is within us." After finding out all he needs, this professor, whose wife left him because she found him to be a boring person, takes a leap into the dark. It's proof that a book can transform a person's life.