Donna Jensen (Gwyneth Paltrow) is a girl from the small town of Silver Springs, Nevada who wishes to see the world and "find herself" in order to get away from her very unhappy home life. Donna grew up in a rural trailer park outside Las Vegas, the only child of a former Las Vegas showgirl, a co-dependent widow and alcoholic, who also lives with an abusive, alcoholic unemployed man. At age 10 during a birthday party thrown by her mother, Donna makes a birthday wish to leave Silver Springs forever.
After graduating from high school, Donna tries to make ends meet by working as a clerk in a local bargain basement department store, while she deals with her long-term high school boyfriend Tommy (Marc Blucas), whom manages the store. But on Donna's 20th birthday, Tommy breaks up with her via a birthday card after revealing that he has gotten a promotion and a move to Tucson, Arizona but does not want Donna to tag along because he considers her "a small town girl".
One day, while drinking alone at a bar, Donna sees on the bar TV set an interview by writer Sally Weston (Candice Bergen) who talks about her reciently published autobiography about Sally's life as a flight attendant which is titled 'My Life in the Sky'. After buying a copy and reading the book, Donna decides to follow her destiny by becoming a flight attendant. Donna leaves Silver Springs, never looking back or saying goodbye to her mother or anyone else she knows.
Donna's first position is at a small, seedy California commuter airline, called Sierra Airlines, that flies only from Sacramento to Fresno, but this success builds her confidence up over the next year. Donna is encouraged to attend open interviews for Royalty Airlines in Los Angeles. She convinces her two co-workers, veteran stewardess Sherry (Kelly Preston) and crafty intern Christine (Christina Applegate), to join her. While Christine and Donna get in, Sherry does not and is forced to go back to Sierra.
Over the next few months, Donna puts her heart and soul into the training camp. Donna meets the flaky and cross-eyed manager of the training school, John Whitney (Mike Meyers). Donna also meets and has the hots for pilot instructor Ted Steward (Mark Ruffalo) whom gives her inspiration and they begin a quiet romance off on the sides. During the training, Donna proves to be a natural, brushing aside most of the other classmates in training.
One evening, Whitney brings his class to Sally Weston's house where Donna finally meets her idol face-to-face for the first time. After seeing around Sally's house of her flight attendant career, Donna is determined to be assigned to the top route: "the New York to Paris, First Class, International". Alas, when the assignments are posted to the graduating class, Donna is shocked to discover that she has been assigned to a commuter route in Cleveland, Ohio. Christine, who had initially struggled with the material and procedures, has inexplicably been assigned the high-priority New York route.
Distraught, Donna never the less settles with her new job and begins a casual romance with Ted who frequently meets with her during his stopovers in Cleveland. Ted is a friendly nice guy, who at one time, introduces his family to Donna whom live in Cleveland (which is touching to Donna who never had any warm or friendly family to begin with). However, Donna however wishes to someday move onto bigger and better things.
A few months later, by chance, Donna runs into Christine in Cleveland and invites her to stay at her apartment instead of a staying in local motel during Christine's stopover, where Donna introduces her to Ted and talks about her current status. But during the visit, Donna knows from previous experience (after catching Christine stealing bars of soap from Sally Weston's house during their visit) that the kleptomanic Christine has stolen things from people's homes and the airlines, but is still shocked when Christine empties her handbag to reveal all manner of Royalty Air items. Even the smallest theft is strictly prohibited by Royalty Airlines, and could mean termination.
Still sure there was some sort of error in her route assignment, Donna turns to Sally Weston for help. Sally looks through the final written exam that Donna took which was below passing, and Donna recognizes the handwriting on the test paper as Christine's. Through a course of events, Donna discovers that Christine had switched their test booklets when they were being handed up to their trainer, John Whitney; Christine's route assignment is rightfully Donna's, and vice versa. When Sally asks to have airline security spy on Christine's flight - to see if she stole any property (a code blue) - Christine gets caught and soon after gets fired by the airline.
Donna gets the chance to re-take her exam and achieves a perfect 100% score, assigning her the New York, First Class, International route that she finally wanted. However, following her "destiny" means deciding between a boyfriend and her career. Over the next year-and-a-half, Donna spends less and less time with Ted and more with her new promotion. When Ted confronts Donna that she is spending more time overseas then with him and his family, he forces her to choose one or the other. Donna chooses her career.
Though she gets all that she wants - Paris, first class, etc. - Donna realizes that she is still not happy. At Christmas time, she takes over a co-worker's shift to Paris in order to let her spend time with her family. Donna spends Christmas Eve in Paris... alone. She misses her boyfriend in Cleveland terribly. After returning to New York on the day after Christmas, Donna meets with Sally Weston to talk about her problem. After Sally's encouragement, Donna returns to Cleveland to meet Ted. She does, and after a heartfelt speech to his deaf grandmother, which Ted overhears, the two kiss and make up.
The movie ends with Donna wishing her passengers well as they land in Cleveland. She has become a Royalty Airlines pilot to be close to Ted... even though there was nothing in her life to suggest that she was at all interested in flying planes.