The story begins in 1992, where Will, a starry-eyed aspiring politician, moves away from Wisconsin and his college sweetheart, Emily (Elizabeth Banks) to New York to work on the Clinton campaign. She gives him a closed packet and asks him to give it to her friend Summer (Rachel Weisz), a reporter. In New York, he meets April (Isla Fisher), the copy girl for the campaign. Before bringing the packet to Summer, Will opens it, it is Summer's diary. Encouraged by his roommate, he reads it, and comes across pages describing a love affair between Emily and Summer. He visits Summer to bring the diary, and meets her roommate and sometimes-lover, her college professor, a famous writer named Hampton Roth (Kevin Kline).
April and Will have a chance meeting outside work, and Will eventually practices a proposal to Emily on April. April is taken aback by Will's words, and replies, "Definitely, Maybe." They go back to her apartment, where April has multiple copies of Jane Eyre in her collection, explaining that her father gave her a copy with an inscription in the front shortly before he died, and the book was shortly lost. She has spent years buying copies of Jane Eyre from secondhand stores, hoping to find the copy her father gave her. Will and April eventually kiss, with Will leaving quickly and berating himself.
Emily visits and Will proposes in the park (first by recounting the story of his parents' engagement, and then by going through the words he said to April), but Emily turns him down and confesses she slept with Will's former roommate in Wisconsin. Will is heartbroken. Time goes by and Bill Clinton becomes president of the United States, and Will moves up to become speech-writer for a candidate to be Governor of New York. April travels the world, and she and Will become pen-pals. Eventually, with the encouragement of Roth, Will and Summer become romantically involved. This ends when she writes unfavorably about the politician Will works for.
In the meantime April returns from her travels as she realized that the man she truly loves is Will. However she met him when he was buying the engagement ring which he was going to give Summer. April is heartbroken, but at that time Will didn't notice it.
Will becomes disillusioned about his choice of profession when Bill Clinton is implicated in the Monica Lewinsky scandal. He hates his job, and starts to drink heavily after finding out that April is dating a new guy. In a drunken rant, he confesses romantic feelings to her, but in the process, ends up having a fight with her, telling her to "go to life-rehab". However maybe because of these words April returned to school.
While walking home after the fight, Will found the copy of Jane Eyre that April's father gave her. He goes to give it to her, but decides against it when he meets her boyfriend Kevin who she is living with.
Summer and Will bump into each other while he is at a cafe, and she invites him to a party. Emily also attends the party, as she now lives in New York. They end up starting up another relationship, and Emily turns out to be Maya's mother and Will's ex-wife. Will explains to Maya that the happy ending all along was Maya and they share a hug and part separate ways.
At home Will signs the divorce papers served to him and then unpacks his things moved from the previous house. By accidence he sees the book he wanted to give April years ago and he decided to meet her at her workplace. After learning that she is now single again, he gives her the book, but when she finds out that he was holding on to it rather than giving it to her immediately, she becomes angry and asks him to leave her office.
Maya is happy that she figured out the story, but also realizes that her father still loves April, as even though Will changed the names of Emily (Sarah in real life), and Summer (Natasha in real life), he did not change April's name. Encouraged by Maya, who wants her father to be happy, he goes to try to win April's heart at her apartment. Though April refuses to open the door at first, she hears Maya demand that Will tell April the story exactly as he told it before. April still doesn't emerge, but as they turn to go back home, she comes outside. Will confesses to April that he held on to the copy of Jane Eyre because it was the only thing he had left of her. As the three enter into April's building, April jumps into Will's arms to kiss him.