It's “A Typical Day" in Dogpatch, U.S.A., and the citizens go about their daily activities: drinking Kickapoo Joy Juice, fishing, and preparing for the Sadie Hawkins Day dance. As usual, sweet, curvaceous Daisy Mae Scragg is pursuing Li'l Abner Yokum who, despite being a strapping, handsome young man, isn't interested in girls or employment. At the fishing hole with his friends, Abner lazily reflects that if he could be anyone in the world, he'd rather be himself ("If I Had My Druthers"). Daisy Mae tells the young men that Senator Jack S. Phogbound has called a “Cornpone Meetin’” in the town square, and they all rush into town. Daisy is frustrated by Abner’s lack of romantic interest ("If I Had My Druthers" Reprise).
At the Meetin', parson Marryin' Sam leads a tribute to Dogpatch's founder, "Jubilation T. Cornpone," a bumbling Confederate general whose leadership was more beneficial to the North than to the South. Senator Fogbound tells the citizens that Congress has declared Dogpatch “the most unnecessary, no-account” town in the country, and they must all evacuate to make room for atomic testing.
Everyone is thrilled that Dogpatch has been picked out of the entire U.S. ("Rag Offen the Bush"). But Earthquake McGoon reminds them that if they leave Dogpatch, the annual Sadie Hawkins Day race won't take place. [In Dogpatch, the only way anyone can be married is if a young woman catches a boy on Sadie Hawkins Day.] Thanks to a $1 bribe, Daisy Mae's unscrupulous relatives, the Scraggs, give Earthquake permission to marry her. Daisy Mae tries to persuade Abner that he deserves to marry a girl like her, and Abner agrees that she should marry a boy like him ("Namely You").
The townspeople lament that Dogpatch has been declared an "Unnecessary Town," and they decide to save the town by proving it contains something necessary. Mammy Yokum suddenly realizes that her homemade Yokumberry Tonic has made her son Abner so strong and handsome. When a short, pudgy government scientist is given a spoonful, he turns into a tall, muscular man. Abner agrees to go to Washington, accompanied by Marryin' Sam, to present the government with the tonic for testing on the scrawny men of Dogpatch.
Greedy, tyrannical General Bullmoose wants to buy the formula for Yokumberry Tonic, and he is angry that Li'l Abner intends to turn the formula over to the government for free ("What's Good for General Bullmoose"). He hatches a dastardly scheme in which his girlfriend, femme fatale Appassionata Von Climax, will catch Abner on Sadie Hawkins Day. Once they're married, Bullmoose will kill Abner, and the formula will belong to his widow, Appassionata.
Abner and Marryin' Sam return to Dogpatch with the happy news that "The Country's In the Very Best of Hands." On Sadie Hawkins Day, General Bullmoose and Appassionata arrive in Dogpatch. They hire Evil Eye Fleagle to help Appassionata catch Abner. The race begins, and the young women of Dogpatch pursue the young men ("Sadie Hawkins Day Ballet”). Though Daisy Mae, with the help of Stupefyin' Jones (any man who looks at her freezes), almost succeeds in catching Abner, Evil Eye Fleagle uses his evil eye to freeze everyone in the race, and Appassionata calmly walks up to Abner and claims him as hers.
In Washington, the scientists testing Yokumberry Tonic dream of a time when life will be totally controlled by science ("Oh Happy Day"). In Dogpatch, Daisy Mae concludes that the reason she couldn't win Abner is that she, at age seventeen, is too old and no longer beautiful, and Marryin' Sam joins her lament ("I'm Past My Prime"). Mammy Yokum has a vision in which she sees Bullmoose and Appassionata's plot to kill Li'l Abner. Daisy Mae asks Earthquake McGoon to go to Washington, D.C. to save Li'l Abner, and she promises to marry Earthquake if he does.
In Washington, an engagement party is being held for Li'l Abner and Apassionata. General Bullmoose has Evil Eye Fleagle on hand; since Fleagle's evil eye can require him to do anything requested, Appassionata won't even have to marry Abner to get the formula. The General is planning to simply have Fleagle use his eye on Abner, get the formula for Yokumberry Tonic, and then order Abner to commit suicide. Mammy and Pappy Yokum, Earthquake, Daisy Mae, and the ladies of Dogpatch all show up to sabotage the party. Daisy May urges Abner to abandon his commitment to Appassionata (“Love In A Home”) but he won’t break his word.
Bullmoose is appalled to have all these hillbillies at his party, but he’ll do anything for the precious Yokumberry recipe (“Progress Is The Root of All Evil”). Fleagle tries to use his evil eye on Abner, but Earthquake holds up a mirror to protect himself and the beam from Fleagle's eye rebounds onto General Bullmoose. Mammy Yokum questions the General, and he reveals the entire plot. The police arrest him and Appassionata.
The women of Dogpatch go to the laboratory to see the results of Yokumberry Tonic. Their scrawny husbands have been transformed into handsome men with no interest in their wives. The scientists explain that this is an unfortunate side effect of the tonic; since it kills a man's romantic interests, it is of no use to the government. The women beg for the scientists to "Put 'Em Back" the way they were. Daisy tells Abner that she's promised to marry Earthquake, but she'd rather marry Abner ("Namely You" Reprise). Softspoken Pappy Yokum tells Abner that he has a secret potion that’ll make Abner want to marry Daisy Mae. Abner agrees to take it once they get back to Dogpatch.
Back in Dogpatch, Marryin' Sam prepares to officiate at Daisy Mae and Earthquake's wedding. Before the wedding, Daisy introduces her filthy relatives to Earthquake, saying that they'll be coming to live with them once they are married. Marryin' Sam begins the ceremony by warning Earthquake of the potential consequences of marriage ("The Matrimonial Stomp"). Abner and Pappy interrupt the ceremony, and Abner takes the potion (Pappy whispers to Mammy that it's really just water) declaring that he wants to marry Daisy Mae. Earthquake now happily relinquishes Daisy Mae to Abner. Men from the government arrive, warning that the atomic bombs are coming soon. As the townspeople try to move the town's statue of Jubilation T. Cornpone, a plaque bearing a declaration by Abraham Lincoln is revealed: because Cornpone's military blunders almost single-handedly allowed the North to win the Civil War, Dogpatch is designated a national shrine. The atomic bombs are cancelled, the scrawny men of Dogpatch return home to their happy wives, the citizens of Dogpatch honor Jubilation T. Cornpone, and Abner kisses Daisy Mae (Finale).