Elizabeth Zott attends UCLA as a PhD candidate where she researches abiogenesis, the study of the origin of life on Earth. One day, Elizabeth’s thesis advisor, Dr. Meyers, gets irate when she questions his judgment and attempts to rape her. Elizabeth fights back by blindly stabbing a pencil behind her, which punctures Meyers’ large and small intestine. Because of the incident, Elizabeth gets forced out of UCLA, while Meyers gets to keep his position. After leaving UCLA, Elizabeth gets a job at the Hastings Institute where she meets Calvin Evans, a brilliant scientist. Although Elizabeth purposely tries to distance herself from Calvin because she does not want him to receive credit for her work, she finds herself falling in love with him. Eventually, she admits her feelings to Calvin, and the two of them begin dating. Everyone else at the office, including Elizabeth’s boss, Dr. Donatti, gossips about their relationship and assumes that Elizabeth is only with Calvin because he is famous. However, Calvin and Elizabeth largely ignore them. Their lives continue to become intertwined when Elizabeth moves in with Calvin and they adopt a dog, Six-Thirty, together.
One day, while Calvin and Six-Thirty are jogging together, a police car backfires and scares Six-Thirty, causing Calvin to stumble and split his skull. Calvin dies of his injuries, and Elizabeth is devastated. After Calvin’s funeral, Elizabeth discovers she is pregnant. Elizabeth is horrified at the thought of having kids, but abortion is not an option in the early 1960s, so she goes through with the pregnancy. However, early in the pregnancy, Donatti fires Elizabeth—he never liked her in the first place, and the pregnancy is the perfect excuse to get rid of her. Jobless, Elizabeth struggles to get by. Most of her income comes from other employees at Hastings who secretly visit her to ask for her help with their research.
Eventually, Elizabeth gives birth to her daughter, Madeleine, whom she raises with the help of her neighbor, Harriet Sloane. Harriet is eager to help, not only because Elizabeth needs her, but also because it allows her to get away from her drunk and violent husband, Mr. Sloane. Madeleine quickly grows into a precocious and socially adept young girl. Because Elizabeth needs a job that pays well, she decides to send Madeleine to kindergarten at an early age. Then, she briefly returns to work at Hastings. Donatti only rehires Elizabeth because he has a mysterious donor who is interested in abiogenesis and wants to keep him happy. However, shortly after returning to Hastings, Elizabeth quits again because Donatti belittles her and demotes her from her previous position.
Desperate for money, Elizabeth decides to take a job at the local television station after an encounter with Walter Pine, one of the producers. Together, Elizabeth and Walter create a cooking show called Supper at Six, which quickly becomes a national sensation. Although Walter tries to make the show a traditional cooking show at the behest of his boss, Phil Lebensmal, Elizabeth refuses to take instruction from anyone. Although she cooks a meal during every episode, she also spends a lot of time discussing the science of cooking and educating her largely female audience about second-wave feminist ideas. Before long, Phil has had enough, and he calls Elizabeth to his office for a private meeting. There, Phil attempts to sexually assault Elizabeth after verbally berating her. However, Elizabeth foils the assault by pulling a large butcher’s knife out of her purse, the sight of which gives Phil a heart attack. The incident puts Phil in the hospital and then recovery for a prolonged period of time, leading to a promotion for Walter. From that point on, Walter allows Elizabeth to do whatever she likes with her show, and it continues to grow in popularity. Although some magazines write nasty articles about Elizabeth and her past, the public generally loves her, and even the president tunes in to watch her show.
Despite the show’s immense success, Elizabeth decides to quit so she can return to her true passion: science. After announcing her retirement from Supper at Six, Elizabeth expects to receive a number of calls from people interested in hiring her. However, the calls never come. Then, one day, Elizabeth receives a call from Miss Frask, one of the few allies she made at Hastings. Frask has recently become the head of personnel at Hastings, and she asks Elizabeth to come into the institute the following day. When Elizabeth arrives at Hastings, she sees Frask with the people responsible for funding her abiogenesis research, Parker Avery and Wilson. Avery and Wilson fire Donatti and offer Elizabeth his role at Hastings. However, Elizabeth rejects the offer because she thinks they only want her because of her relationship with Calvin.
Avery takes Elizabeth aside and reveals her true identity and explains why she is interested in Calvin: it turns out that Avery is Calvin’s birth mother, whom Calvin long believed to be dead. Avery also thought Calvin was dead because a bishop at the boys’ home where he grew up lied in order to receive more funding. Avery only discovered Calvin was alive after he became a famous scientist. In an effort to reconnect with her son, she started funding the Hastings Institute. However, before they could reunite, Calvin tragically died. After hearing Avery’s story, Elizabeth accepts the job at Hastings and invites Avery back to her home so she can meet Madeleine.