While Christmas shopping at Bloomingdale's in New York City, Jonathan Trager meets Sara Thomas when both try to buy the same pair of black cashmere gloves. Despite both being in relationships, a mutual attraction leads them to have dessert at Serendipity 3 where Sara explains that she lets fate's "little signals" determine many of her life decisions. After separating, they meet again when each returns to the restaurant to retrieve something they forgot. After ice skating, Jonathan convinces Sara to give him her number, but when the wind blows it out of his grasp, Sara thinks it is fate telling them to back off. After Jonathan disagrees, Sara decides to let fate reunite them: she has Jonathan write his number on a five dollar bill then uses it to buy breath mints and promises to sell her copy of Love in the Time of Cholera in which she will write her name and number. As one last experiment, Sara tosses Jonathan one of the gloves, they board separate elevators in the Waldorf Astoria and agree that if they arrive on the same floor, they are meant to be together. They each pick the same floor, but Jonathan is delayed finding Sara, leading her to believe that the experiment failed. Disappointed, they separate.

Years later, Jonathan is an ESPN producer engaged to Halley and Sara is a therapist living in San Francisco, engaged to internationally-renowned musician Lars. Jonathan runs across his cashmere glove, so he embarks on a search of the city with his best friend, Dean, to find Sara. Meanwhile, Sara, stressed by the wedding planning and Lars’ focus on an upcoming world tour, travels to New York with her best friend Eve to find Jonathan. After nearly crossing paths with Jonathan throughout the day, Eve and Sara have dessert at Serendipity where Eve convinces Sara to give up her search. As Eve leaves, she picks up the 5 dollar bill with Jonathan's number on it that was left as their change. They catch the same cab that Jonathan and Dean exited while searching for Sara. After finding that a bridal shop next to Serendipity now occupies the address of a roommate finder service Sara once used, Jonathan sees it as a sign that he should marry Halley.