The story opens in the late 1950s, when Margaret Keane packs up the car with her daughter and their personal belongings, and leaves her husband to start a new life in San Francisco. There, Margaret quickly reconnects with her old friend DeeAnn, and falls head over heels for Walter, an artist and part-time real-estate broker who soon shows great interest in her unique paintings of small children with strikingly expressive, saucer-like eyes. Before long, the two are married, and Walter is claiming credit for Margaret's increasingly popular paintings.
With the money rolling in, Margaret initially agrees to go along with the ruse, but the closer she gets to her new husband the more she begins to realise that he's little more than a smooth-talking scam artist. Later, riddled with guilt over the fact that she's been deceiving her own daughter as her paintings become a pop-culture phenomenon, Margaret leaves the increasingly abusive Walter, and moves to Hawaii. Only then does Margaret gain the confidence to reclaim the works that have been credited to her husband, even when doing so entails going before the judge and proving that she and she alone created the enchanting children with the big eyes.