It's 1922, and Millie Dillmount has arrived in New York City from Salina, Kansas. She is scared and excited to be there ("Not for the Life of Me/Thoroughly Modern Millie.") Surrounded by "moderns," Millie is a fish out of water. Determined to make it, she raises her skirt, bobs her hair and joins the "thoroughly modern" crowd of New York.

Millie is then mugged and asks a passerby, Jimmy Smith, for help. He tells her to go back to Kansas and, when Millie refuses, suggests she check into the Hotel Priscilla — a rooming house for actresses. The defiant Millie plans on staying and making her mark in the big city ("Not for the Life of Me – Tag").

A week later, at the Hotel Priscilla, the girls bemoan not getting any acting roles, but they aren't leaving the excitement of the city. Ethel brings in a newspaper that has a headline of "White Slavery," going on to say that many young girls, mostly orphans, have suddenly disappeared without anyone noticing.

The hotel is run by Mrs. Meers, a former actress-turned-criminal, who has adopted the guise of a kindly Chinese proprietress to mask her real profession: white slavery. She gives Ethel a telegram that says her great uncle has died, and she is now an orphan... making her Mrs. Meers' next victim.

Millie enters and is told she must leave because she is behind on her rent. Lucky for her, Miss Dorothy Brown arrives at the Hotel Priscilla, and Millie makes a deal to share her room with the newcomer if she pays the rent. Dorothy agrees, and they quickly become friends as they learn about each other's desires. Mrs. Meers offers Ethel's newly vacated room to Miss Dorothy, who reveals that she is an orphan. Mrs. Meers is so happy about this news that she allows Millie to stay.

In the laundry room of the hotel, Ching Ho and Bun Foo are folding towels when Mrs. Meers enters and tells Bun Foo to take Ethel to Buddha (her buyer in the slave trade) and collect the money. Ching Ho is ordered to take a snack to the new arrival, Miss Dorothy. We discover the boys are working here to save money to bring their mother over from Hong Kong ("Not for the Life of Me – Reprise"). Later that afternoon, Millie arrives at the Sincere Trust Insurance Company to interview with Trevor Graydon the Third, who needs a stenographer... and who is also single. She plans to find a successful man for whom to work... and eventually marry. Miss Flannery, the office manager, makes it clear that she doesn't like this "modern" Millie. In spite of Flannery, Millie aces the interview and gets the job ("The Speed Test").

At the hotel, Ching Ho sees Miss Dorothy for the first time and is instantly smitten. Mrs. Meers' attempts to poison Miss Dorothy with an apple are thwarted.

Millie takes the girls out on the town to celebrate her new job. While looking for a speakeasy, they run into Jimmy Smith, who gets them into an exclusive club. A wild dance ensues right before the joint is raided. With time in jail to think, Jimmy reconsiders his feelings towards Millie ("What Do I Need with Love").

The next morning, Jimmy invites Millie to a Yankees game, which she turns down, explaining how she can't miss work since she is trying to get her boss to marry her. They are nose-to-nose when Jimmy grabs Millie and kisses her. Millie is surprised and kisses him back. Jimmy exits in a panic, leaving her alone to figure out how she feels ("Jimmy"). On cloud nine, she heads home and spots Jimmy sneaking out of Miss Dorothy's room. Millie is in shock.

Back at work, Millie refuses to take Jimmy's calls. Her sisterhood of stenographers, Flannery included, supports her stance ("Forget about the Boy").

Millie tries to get Graydon to notice her, but to no avail. Miss Dorothy arrives and reminds Millie of last night, but the two ladies eventually make up. Graydon enters and sees Miss Dorothy; they stare at one another and find love at first sight ("Ah! Sweet Mystery of Life/I'm Falling in Love with Someone").

Jimmy has crawled out onto a window ledge at Sincere Trust in order to avoid Flannery and to get Millie's attention. He declares his feelings for her ("I Turned a Corner"), and she echos them back. They decide to go on a real date. In the midst of a quartet of Millie, Jimmy, Graydon and Miss Dorothy professing their love, Ching Ho enters and professes his love for Miss Dorothy.

Meanwhile, back at the Hotel Priscilla, Mrs. Meers is still stalking Miss Dorothy... this time with pesticide spray guns. When Ching Ho balks, Mrs. Meers reminds him that he is trying to get his mother to New York ("Muqin").

That night, at Cafe Society, Millie and Jimmy listen to the show ("Long as I'm Here with You") from the kitchen, where they are washing dishes to pay their bill, which they didn't have the money to cover. Millie tells Jimmy that they are not right for each other because she doesn't want a lifetime of washing dishes in a restaurant kitchen. Jimmy tells Millie that her plan to marry her boss is flawed because marriage has everything to do with love. Jimmy asks Millie to marry him, and a confused Millie abruptly leaves Jimmy to consider his advice ("Gimme Gimme").

Millie discovers a distraught Mr. Graydon: Miss Dorothy has stood him up. Jimmy, who is looking for Millie and runs into both of them, is convinced that something is very wrong. The three conclude that Mrs. Meers must be behind the white slavery ring and hatch a plan to stop her.

Miss Flannery enters the Hotel Priscilla disgusied as an ingenue, wearing a blond wig and carrying a beat-up suticase. Although Mrs. Meers thinks the new girl is a little long in the tooth to be an orphan, she welcomes her to the hotel. Meanwhile, Ching Ho vows to help the gagged and tied-up Miss Dorothy.

Mrs. Meers makes a phone call to Buddha about the new orphan and gives the others all the proof they need to get Mrs. Meers put behind bars ("The Speed Test – Reprise"). They demand to know where Miss Dorothy is, discovering her in an embrace with Ching Ho, who has rescued her from an unspeakable fate ("Ah! Sweet Mystery – Reprise"). Miss Flannery escorts Mrs. Meers to the police station.

Jimmy proposes to Millie and, even though he is poor, she accepts... only to find out that Jimmy is Herbert J. Van Hossmere the Third, and Miss Dorothy is Jimmy's sister. As the couples embrace, the stage is filled with "moderns," echoing the opening of the show ("Finale"). A new young girl in her Sunday best carrying a suitcase surveys her surroundings with awed excitement and strikes Millie's opening pose.