Me Before You begins with its protagonist, Louisa Clark, losing her steady job at a cafe. Since her family's financial situation is increasingly worrisome, she takes the best available job in her small town: care worker for a quadriplegic man. The man is Will Traynor, a former London businessman who has been seriously injured in an accident. Will is bitter when Lou first meets him, and subjects her to cruelty and ironic asides. However, the two eventually begin to connect, sharing jokes and treating one another with straightforward honesty. Will encourages Lou to explore interests outside of her comfort zone, while Lou gives Will practical assistance and helps him to feel less depressed.
After several weeks on the job, Lou overhears a conversation between Will's mother and sister. She learns that Will has attempted suicide once and is still determined to commit physician-assisted suicide. He has agreed with his mother that he will wait six months before going to Switzerland to take his own life. Lou, who has grown fond of Will, is so upset that she nearly quits her job. She returns on the condition that she be allowed to take Will on a series of "adventures" in the hopes of brightening his outlook and convincing him to stay alive.
Lou, accompanied by Will's nurse Nathan, takes her charge on a series of outings with moderate success. They attend horse races, concerts, and art gallery shows, all while becoming closer with one another. Louisa eventually reveals to Will one of the reasons for her cautious personality. As a teenager, she endured a traumatic sexual assault on the grounds of the town's medieval castle. Afraid of taking risks that might put her in a similar situation, Lou stays close to home and avoids new opportunities. Will comforts her and helps her to overcome this event in her past so that she can live more adventurously.
While the two main characters are growing closer and learning from one another, Lou's life outside of work begins to fall apart. Her father loses his job, and her sister decides to return to university, putting the family in more financial distress. Various logistical conflicts result in Lou having no place to sleep in her family's busy house. She moves in with her boyfriend, Patrick, but their relationship is increasingly distant and unsatisfying. This is largely due to Patrick's obsession with triathlons and fitness. Lou and Patrick break up after Patrick accuses Lou of being in love with Will. Knowing she needs a place to stay on weekends, Will invites Lou to spend the night in his family's house.
When Will's six-month waiting period is almost over, Lou takes him on vacation in a final effort to convince him to live. She plans a trip to California, but Will becomes sick, making the trip impossible. At the last minute, Lou plans another trip to Mauritius. She, Nathan and Will spend a blissful vacation at the beach. On their final night, Lou and Will kiss. Will, though, puts a stop to the kiss and tells Lou about his plan to commit suicide. She tells him that she has been aware of the plan and tries to convince him to live so that they can be together, but Will refuses. He asks Lou to accompany him to Switzerland for his scheduled death. Lou reacts angrily, refusing to speak to Will when they return and refusing to go to Switzerland.
Lou is distraught when she returns home, in spite of her family's best efforts to cheer her. Moreover, reporters swarm her house, pursuing a story on the hot-button issue of assisted suicide. She receives a call from Will's intimidating mother, Camilla, begging her to come to Switzerland. Lou, having realized that she wants to see Will before he dies, leaves in spite of her mother's opposition to the suicide and her daughter's involvement. She arrives in Switzerland and has a final conversation with Will in which they express their love for one another. Lou gives Will her forgiveness and cries beside him, trying to show Will that he is loved in his final moments.
After a time-jump, Lou reads a letter from Will at a cafe in Paris. He explains to her how to obtain the fortune he has left her, and commands her to "live boldly" by being adventurous and expressing herself. Lou finishes the letter and then stands up to explore Paris, apparently ready to live the life Will has encouraged her to live.