Henry Roth, a marine veterinarian at Sea Life Park Hawaii on Oahu, only dates tourists to avoid any serious commitments. His closest friends are Ula, a marijuana-smoking Islander; Alexa, his androgynous assistant; Willy, his pet African penguin; and Jocko, a walrus that lives at the park.
One day, Henry's boat breaks down, and while waiting for the Coast Guard at the Hukilau Café, he encounters art teacher Lucy Whitmore constructing architectural art with her waffles. Assuming she is a local, which prevents him from introducing himself, he unsuccessfully attempts to return to his womanizing routine. The next day, he returns to the café and re-encounters Lucy; they instantly connect over breakfast and Lucy offers to meet him again for breakfast the next morning.
The next day, however, Lucy unfortunately shows no recollection of ever meeting him. The restaurant owner Sue explains to Henry that the year before, Lucy and her father Marlin traveled to the North Shore to pick a pineapple for his birthday. While they were returning, a cow wandered through a broken fence and onto the road, and the ensuing car accident resulted in Lucy being diagnosed with anterograde amnesia, whereby she remembers everything up until the night before the accident; although her memory functions normally during the day, her daily experiences are lost when she sleeps and she wakes up the next morning thinking that it's Sunday, October 13. To spare her from horrifically reliving the accident, Marlin and Doug, Lucy's steroid-addicted brother, re-enact Marlin's birthday daily.
Despite Sue's warning, Henry attempts to get Lucy to have breakfast with him several times, but when he unintentionally offends her one day, he follows her to her house to apologize, but Marlin and Doug instruct him to leave her alone. However, Alexa advises Henry to look for a loophole in said instruction. Heeding Marlin's specific orders to avoid the café, Henry meets Lucy on the road through the following days, most of the time managing to successfully impress her over multiple "first" dates and "chance" encounters. Later, Marlin and Doug permit Henry to continue when they discover Lucy regularly singing the Beach Boys' "Wouldn't It Be Nice" in her painting studio just on the days Henry managed to meet her, the first major change in her routine since the accident.
One day, Lucy notices a police officer writing a ticket because of her expired license plates. With the ruse exposed, she is distressed to learn that her friends and family have maintained the charade for so long. However, while analyzing her reaction, Henry surmises that her strongest reactions are to feeling betrayed by her loved ones, rather than the actual memory loss. He devises a new strategy to let her know about the truth by creating a video with her friends to explain the situation calmly; rather than allowing her pre-accident routine to continue, they plant the video in her room with a note to play it upon awakening. The strategy succeeds, allowing Lucy to process the events of the video and simultaneously be updated on current events, including her relationship with Henry. The couple's relationship blossoms via this method, and they continue to refine the process while enduring some humorous setbacks. However, when Lucy discovers that Henry has decided to abandon 10 years of planning for his research study of walruses in Bristol Bay to help manage her condition, she decides that they need to end their romantic relationship. Henry reluctantly helps her destroy her journal entries about their relationship, effectively erasing their time together.
Some weeks later, while Henry is preparing to leave for his research study, Marlin informs him that Lucy is teaching an art class at an institute. As a parting gift, he gives Henry a Beach Boys CD; Henry suddenly realizes that Lucy's singing of "Wouldn't It Be Nice" occurred on days when they "met", indicating new learned memory retention. Despite not remembering him when he arrives at her class, she happily reconciles with him by revealing that she has dreamt of him nightly via her illustrations of some of their adventures. Sometime later, she awakens and plays the tape marked "Good Morning Lucy", but it noticeably ends with her and Henry's wedding. Realizing that she is on his boat, which finally made it to Alaska, she goes up on deck, meeting their young daughter Nicole.
Adam Sandler as Henry Roth, a marine veterinarian with a habit of wooing women and a fear of commitment.
Drew Barrymore as Lucy Whitmore, Henry's love interest with short-term memory loss.
Rob Schneider as Ula, Henry's marijuana-smoking, wealthy native Hawaiian assistant and best friend; who is unhappily married to an overweight native woman and has five young, athletically talented children.
Sean Astin as Doug Whitmore, Lucy's older brother, a lisping, steroid-dependent bodybuilder.
Blake Clark as Marlin Whitmore, Lucy's widowed father, a professional fisherman.
Lusia Strus as Alexa, Henry's ambiguously gendered German assistant.
Dan Aykroyd as Dr. Joseph Keats, a physician specializing in brain disorders.
Amy Hill as Sue, the Hukilau café manager and friend of Lucy and her late mother.
Pomaika'i Brown as Nick, the Hukilau café chef and Sue's husband.
Allen Covert as Ten-Second Tom, a hospital patient with severe memory impairment.
Missi Pyle as Noreen, a tax attorney Henry meets at a bar but then tries to fix up with Alexa.
Maya Rudolph as Stacy, pregnant friend of Lucy's at the beach party.
Lynn Collins as Linda
Kevin James as Factory worker