Strepsiades, the father of spend-thrift Pheidippides, cannot sleep because he is worried about the debts that he has incurred because of Pheidippides's expensive passion for racehorses. Strepsiades calls in a Slave to bring him his accounts so that he may tabulate his debts. Looking over his debts, he becomes enraged and his voice wakes Pheidippides. Strepsiades begs Pheidippides to refrain from his expensive ways and begs him to enroll in the new-fangled school next door wherein he may learn about esoteric natural sciences as well as sophistry that might help him outwit their creditors in court. Pheidippides stubbornly refuses, leaving Strepsiades to enroll himself.

Strepsiades arrives at the school and meets a Student who tells Strepsiades about Socrates's new experiments involving insects and astronomy. The Student shows Strepsiades the other Students of the school, bent over in their studies so that they may study geology with their faces and astronomy with their behinds. While the Student is showing Strepsiades their maps, Socrates appears in a balloon-basket hanging in mid-air. Socrates explains that the contraption helps him "suspend" (I.i.230) his judgment and open his mind to new ideas. Strepsiades explains his plight and asks for guidance. Socrates enlightens Strepsiades, proving to him that the gods do not exist and that the weather patterns are produced by a Chorus of Clouds. Socrates fleeces Strepsiades of his coat and hustles him inside.

In Strepsiades's absence, the Chorus of Clouds sings a song in defense of the play, berating the audience for not rewarding it when it was first produced. The Chorus praises the moral intent of the playwright and the important examples his satire teaches in troubled times.

Socrates and Strepsiades reemerge and discuss the gender of nouns. Socrates puts Strepsiades in a louse-ridden bed to contemplate. After much agony, Strepsiades shares his ludicrous theories for how to win his court case. Socrates despairs and calls him a worthless pupil. The Chorus of Clouds convinces Strepsiades to enroll his son instead.

Strepsiades runs home and quizzes Pheidippides with his newly acquired sophistry. He drags Pheidippides to the school where the two Arguments, Just and Unjust, argue over the proper model for boys' education. Just suggests a model of education based on traditional poetry and physical fitness, but his descriptions falter when his libido overwhelms him. Unjust unravels Just's argument with examples drawn from myth and other trivia. Just is thoroughly flustered and Unjust is granted Pheidippides as a pupil. The Chorus of Clouds intimates that Strepsiades's forcible education of Pheidippides will be his own undoing before turning to the audience, wheedling, bribing, and even threatening them for their approval of the play.

Strepsiades's day in court draws near and he goes to pick Pheidippides up at the school. Socrates promises that Pheidippides is well-versed in their special brand of specious learning which Pheidippides soon demonstrates when he attacks the idiom the day of "Old and New" as an instance of hysterical paradox. While Strepsiades is gloating that his son is a splendid example of Unjust Argument, he is visited by two creditors. The First Creditor demands that Strepsiades appear before the court. Strepsiades quizzes him about the gender of nouns and refuses to pay his debt on the basis of the First Creditor's apparent ignorance. The Second Creditor appears woefully wringing his hands and begging Strepsiades. Strepsiades berates him for his belief in the gods and uses the Unjust Argument to deny responsibility for any interest on his debt. He flogs the Second Creditor until he runs off. The Chorus sings a song warning that Strepsiades's "evil" (II.i.1303) will soon come back to him.

Sure enough, as their song winds down, Strepsiades bursts from the house while being beaten by Pheidippides. The two have been quarreling over the recitation of traditional poetry. Pheidippides defends his beatings using sophistry. Strepsiades mourns that he has exchanged Pheidippides's obsession with expensive horses for his obsession with sophistry and rhetoric, which is proving to also have its price. Strepsiades blames the Chorus of Clouds for misleading him and they defend themselves by asserting that their deception taught Strepsiades a lesson. Strepsiades concedes that he has been wrong but still hungers to do violence against Socrates and the school. He summons his slave Xanthias and the two run over to the school and set fire to the roof. Chaerephon and a Second Student cry out from within as the building burns and finally rush outside. Strepsiades crows his "Revenge" (II.i.1506) and chases off the last of the Students by throwing rocks. The Chorus appraises the scene and takes its leave.