Sophie Hall (AMANDA SEYFRIED) is a fact checker for the New Yorker, but dreams of being a writer. She gets the chance when she and her restaurateur fiancé, Victor (GAEL GARCIA BERNAL), travel to Verona, Italy for a pre-wedding vacation. Since his eatery in New York City is about to open, he's thrilled with meeting various food suppliers and vintners, thus leaving Sophie to fend for herself.
After seeing various lovelorn women leaving romantic letters on the Juliet wall -- so named after the star-crossed lover of Shakespeare fame -- and then following the women who collect those letters, Sophie becomes acquainted with the Secretaries of Juliet. Learning that they write advice letters back to those original women about their love lives, Sophie joins them in their endeavor. When collecting the next batch, she discovers a letter from a young woman, Claire, wondering about what will happen with her and the love of her life, someone named Lorenzo.
Despite that letter being around fifty years old, Sophie decides to take a chance and write back with her advice. Little does she expect, however, that Claire (VANESSA REDGRAVE) will actually show up, with her young adult grandson, Charlie Wyman (CHRISTOPHER EGAN), in tow.
Despite him thinking it's a ridiculous idea, Sophie convinces Claire that they should try to find Lorenzo Bartolini. The only problem is they don't know if he's still nearby or even alive, let alone the fact that there are 74 men in the general area with that name.
Undeterred, the two women set out to find the real one, all while Charlie protests but eventually begins to soften toward Sophie who similarly begins to develop feelings for him, especially with Victor being too busy to spend any time with her on their vacation.