Amélie Poulain (AUDREY TAUTOU) is a young woman who works as a waitress at The Two Windmills, a small café in the Montmartre district of Paris. Having lost her mother at a young age and then being raised by her cold physician father, Raphael (RUFUS), Amélie has grown up as an innocent with a vivid imagination.
Like her painter neighbor, Raymond Dufayel (SERGE MERLIN), known as the glass man for his brittle bone condition that's kept him in his home for the past twenty years, Amélie lives in her own world, observing but rarely interacting with others outside the café where she works for Suzanne (CLAIRE MAURIER), the owner, and serves regulars such as Hipolito (ARTHUS DE PENGUERN), a failed writer.
That changes when she accidentally finds a small, hidden tin filled with childhood mementos in her apartment. Setting out to return them to their now middle-aged owner, Dominique Bretodeau (MAURICE BÉNICHOU), Amélie revels in the anonymous joy she feels upon seeing him rediscover himself. From that point on, the young woman decides to make it her mission to help others find happiness in their lives.
Among those she targets is Madeleine Wallace (YOLANDE MOREAU), a longtime widow who still longs for her husband and suddenly starts receiving long lost letters from him, thanks to Amélie. Then there's Georgette (ISABELLE NANTY) the hypochondriacal tobacconist at the café whom she slyly fixes up with Joseph (DOMINIQUE PINON), the bitter ex-lover of Gina (CLOTILDE MOLLET), another waitress at the café.
Amélie also decides to help Lucien (JAMEL DEBBOUZE), a friendly man who's always picked on and insulted by his employer, Collignon (URBAIN CANCELLIER), the local grocer, via a series of practical jokes that soon cause the mean man to question his sanity. She even tries to brighten the life of her father by having his beloved gnome figure travel the world.
Amélie also decides to cautiously approach Nino Quicampoix (MATHIEU KASSOVITZ), a young man who she sees as something of a kindred spirit and to whom she's attracted. Although he holds down various jobs, Nino's odd hobby of collecting discarded and torn up pictures from photo booths around the city fascinates Amélie and she sets out, in her own imaginative and highly complex way, to finally meet this man. As she does so and continues in her efforts to help others, she spreads joy through the lives of those she touches.