Holly and Gerry are a happily married couple living on the Lower East Side of Manhattan until Gerry dies of a brain tumor. Deeply distraught, Holly withdraws from her family and friends until they descend upon her on her 30th birthday. They are determined to force the young widow to face the future and decide what her next career move should be. As they rally around Holly and help organize her apartment, a cake is delivered, and on it is a message from Gerry. It proves to be the first of several — all ending with the sign-off P.S. I Love You — he arranged to have delivered to her after his death. As the seasons pass, each new message fills her with encouragement and sends her on a new adventure. While Holly's mother Patricia and her best friends Denise and Sharon are concerned Gerry's letters are keeping Holly tied to the past, they are in fact pushing her into the future. With Gerry's words as her guide, Holly slowly embarks on a journey of rediscovery.

Gerry pre-arranged for Holly, Denise, and Sharon to travel to his homeland of Ireland, and while there they meet William, a singer who strongly reminds Holly of her deceased husband and coincidentally was his childhood friend. During the vacation, Denise announces she's engaged and Sharon reveals she's pregnant, and the news causes Holly to relapse emotionally and once again withdraw into herself.

Holly eventually enrolls in a fashion course and discovers she has a flair for designing women's shoes. A newfound self-confidence allows her to emerge from her solitude and embrace her friends' happiness. She decides to take her mother on a trip to Ireland, and as the film ends the audience is left with the notion that Holly has opened herself up to the journey that the rest of her life will be, and wherever it takes her; she finally abandons her fear of falling in love.