A prologue is presented to the audience explaining the commedia style in which the show is to be performed, and a short description is given of each character. Androcles is the protagonist and is introduced to the audience in the beginning of the play. He describes his current situation, and describes how miserable he is. Meanwhile the two lovers, Lelio and Isabella, profess their love for one another. Lelio asks for Isabella's hand in marriage but Pantalone (Isabella's uncle) refuses to let them marry because he does not wish to sacrifice Isabella's gold dowry. Pantalone decides to bury Isabella's dowry so that he can keep it for himself. The Captain enters and is told to keep guard by Pantalone over Isabella so that he can bury her dowry without her knowing where it is.
Meanwhile, Androcles and Isabella manage to trick The Captain and they escape together to find and retrieve her dowry. Lelio and Isabella find each other and decide to run away together, however while doing so, Androcles discovers that he is still holding Isabella's dowry and that he is now a run away slave. If caught, he will be fed to the lions as a warning to other run-away slaves. Androcles panics and runs into the forest.
While looking for somewhere to hide, he stumbles into a cave and comes face to face with a lion. At first the two have a misunderstanding but after resolving some communication problems, Androcles discovers that the Lion has a thorn stuck in his paw. Androcles removes the thorn for the Lion and a friendship blooms, however just when this relationship starts to develop, Androcles is captured by The Captain and Pantalone.
The Lion follows Lelio and Isabella back to Rome to assist Androcles any way he can. The lovers discover where Androcles in the Colosseum where he is set to fight against the many dangers that lurk within. The lion that emerges from the pit to eat him is the very same one that Androcles had helped in the forest. The two old friends embrace each other and in the spirit of a happy ending, the Emperor of Rome decides to free both of these prisoners. Pantalone is told to return Isabella's dowry and The Captain is sent away to a foreign land to fight. Hence, the characters with good intentions received happy endings unlike those who only had their best interests at heart.