Panty and Stocking are sent to investigate several cases of people getting eaten by toilets, which are caused by a ghost bent on covering Daten City in feces.

Panty and Stocking chase after a ghost with the ability to possess vehicles. However, Panty's underwear (which transform into her weapon) get stuck on the ghost's head, making it difficult to get them back without damaging them.

While investigating a series of disappearances at Daten City High School, Panty and Stocking encounter Queen Barby, the cheerleading team captain whose reign as the most popular student is threatened by the Anarchy sisters. With the help of the teenage occult geek Brief, Panty and Stocking expose Barby as the Ghost behind the school's disappearances.

At the preview of her and Stocking's first feature film, Panty screens a pornographic film she once starred in, which leaks to the public. With her celebrity lifestyle at risk, Panty travels the world with Stocking and destroys every copy of the porn in existence save for one, which the sisters decide to keep for themselves. But when Panty reveals she edited out all of Stocking's scenes in their film, Stocking gets revenge by uploading the last porn copy online.

Panty and Stocking get into a heated argument over a missing cup of pudding and go their separate ways. However, they are forced to put their differences aside to defeat a pair of Ghosts who work as a team.

The Ghosts of vengeful sperm cause a shortage of tissue paper, rendering the men in Daten City incapable of wiping themselves after ejaculating.

Stocking finds herself gaining weight and goes on an intense diet, but she only keeps getting fatter until she balloons into a giant. When the cause is revealed to be from an obese Ghost who refuses to diet, Stocking sets out for revenge. Upon defeating the Ghost, Stocking returns to her original figure.

Daten City High School holds a lingerie run in which participants must race in their underwear. The run is interrupted by a Ghost who eats underwear, including Panty and Stocking's weapons, so Panty must resort to using whatever underwear she can find.

A recreational nose-picking fad spreads across Daten City thanks to a man named Oscar H. Genius, who invites the citizens of Daten City to a blimp party. However, Genius turns out to be a Ghost intent on ramming the blimp into the moon using the passengers' collective nosebleeds.

In the gloomy town of Little Tokyo neighboring Daten City, a struggling office worker named Terao is denied his chance to attend his young daughter's birthday party and forced by his co-workers to drink a mountain of beer, causing him to create a Ghost made of vomit. Panty and Stocking defeat the Ghost and decide to help Terao with his troubles by giving him their autographs as a present for his daughter, who is an avid fan of the Anarchy sisters.

Panty and Stocking arrive at school to find that a strict academic regime has been established by the mayor's daughters, the Demon sisters Scanty and Kneesocks, and are banished to the lowest class in school. Together with Brief, Panty and Stocking discover that Scanty and Kneesocks are demons who are running a factory that produces an army of fake Ghosts beneath the school. A destructive battle ensues, with the Anarchy sisters defeating the Daemon sisters by destroying the stone that powers the factory.

Panty and Stocking's sibling feud escalates into all-out war when they eat the cores of two warring alien robots and transform into robots themselves. When the alien robots decide to join forces to destroy the human race and merge into a Ghost, Panty and Stocking are once again forced to work together to defeat the Ghost.

Garterbelt gets angry at Panty and Stocking for wasting money, so the sisters make a bet to raise $3 million in three days. Getting jobs proves difficult for them, so they resort to going to a casino run by Scanty and Kneesocks, who rig their games to ensure the angels will lose. The Anarchy sisters eventually run out of money, but by selling their clothes to onlookers, they manage to play long enough to break through the Demon sisters' scheme and earn their $3 million.