Two shabby men who seem to be old friends meet on the side of a country road near a leafless tree. The first, Estragon, has been beaten up, and the second, Vladimir, suffers from groin pain and frequent urination. They consider repenting, though they don't know what for, and they discuss the different views in the Bible of the two thieves crucified with Christ. Getting bored, they consider leaving, but Vladimir says they are waiting for Godot. They have asked him for something, though they aren't sure what, and they are waiting for a response. They consider hanging themselves as a diversion to pass the time or to speed up time, but they worry about one of them surviving alone. In the meantime, there is "Nothing to be done."
Vladimir and Estragon hear a "terrible cry" just before two travelers arrive. Pozzo, a wealthy landowner, stops to eat and talk to the two men but mostly takes pleasure in hearing himself talk. He roughly orders around and abuses Lucky, a slave whom he keeps on a rope. Lucky is unresponsive except when following Pozzo's orders, and kicks Estragon when he tries to comfort him. When he is ordered to think, however, Lucky produces a jumbled speech that verges on profound meaning. He becomes increasingly passionate until the others angrily attack him to make him stop. Lucky collapses, and to be revived, he must be reacquainted with the burdens he carries. After the sun sets, he and Pozzo continue on their journey.
Vladimir reveals that he and Estragon have met Pozzo and Lucky before—at least he thinks so. A boy arrives with a message from Godot—he will not come this evening, but "surely tomorrow." It seems the two friends have also heard this message before, although the boy claims not to have come yesterday. Their questions about Godot reveal how little they know about the person they've been waiting for. They ask the boy to tell Godot he has seen them. The moon rises, and they decide to find a place to sleep, but neither moves.
When Vladimir and Estragon return, the tree has a few leaves on it, which is astounding for Vladimir and confusing for Estragon. Estragon has been beaten again, and he is angry that Vladimir, who is feeling better, seems happy without him. He suggests they part ways, but Vladimir discourages him. Vladimir reminds Estragon of their encounter with Pozzo and Lucky "yesterday," of which Estragon has only vague recollections. Estragon sees the world as a "muckheap," and their conversations—to pass the time—linger on describing the dead, who "make a noise like feathers." They also debate the value of thought, ultimately deciding it has little worth.
When Vladimir points out the change in the tree, Estragon denies that they were in this place yesterday. Certainly all is not exactly as they left it, including Estragon's boots, which he claims are now a different color and size. Estragon becomes increasingly bored and wants to go, but when he does leave, he returns immediately, fleeing from someone who seems to be coming from all directions. When Vladimir looks, however, he sees no one. After Estragon calms down, they continue their random conversations and activities to pass the time as they wait for Godot.
Lucky and Pozzo arrive again, but they are much different. Pozzo has gone blind, which turns him into a pitiful figure who must rely on Lucky's guidance and support. He falls whenever Lucky does. Indeed, both fall as they arrive and seem unable to get back up. When Vladimir and Estragon try to help them, they also fall and cannot get up, until a passing cloud distracts them. They help Pozzo up and suggest that Lucky might perform for them again. But Lucky has been struck dumb (left unable to speak). Pozzo also has no memory of any previous meetings with Vladimir and Estragon. After letting Estragon avenge himself on Lucky, Pozzo and Lucky continue on, falling down again as they go.
While Estragon naps, a boy arrives with the same message from Godot: he cannot come tonight but will tomorrow "without fail." The boy says he did not come yesterday and doesn't know if his brother, who is sick, did. Vladimir again asks the boy, more desperately this time, to tell Godot that he has seen him, but the boy runs away without confirming that he has seen him. Night falls and Estragon wakes up. He and Vladimir again consider hanging themselves, but once again they have no rope. They resolve to bring some tomorrow when they return to wait for Godot, and agree to go for the night. Neither moves.