The Event in After the End is the apocalyptic event that ended the Old World.
The exact nature of the Event is unknown, and a topic of speculation even in the world. The only known fact is that the Event hit humanity in an unspecified moment before 2078, when the first known Pope of the Papacy of St. Louis, Petrus Romanus, is said to have taken position. It's made clear that the Event hit the entire world.
The pandemic theory
It is possible that the world was ravaged by a pandemic illness that caused the death of the majority of the global population. The existence of a deadly illness called Red Death seems to point in this direction.
The asteroid theory
If the Earth was struck by a great meteor, similar to the one that caused the dinosaurs' extinction, it is possible the damage would cause a dramatic loss in human population. The faith of the Fallen Star venerates an angel that fell from the sky, which seems to indicate that at least a small asteroid did hit Earth during or in the time following the Event.
The nuclear winter theory
If the Event was manmade, then nuclear winter becomes the most likely cause of it. Nuclear winter could indeed cause enormous damage to the world. The Aphite faith may also be linked to this theory.
The Nuclear Winter - Leibowitz Sub-Theory
After the End draws many details regarding the Catholics from the novel 'A Canticle for Leibowitz' which provides it's own explanation for the event. The novel's background state that Leibowitz was a Jewish electrician before a nuclear war devastated the planet however the war it's self did not plunge Humanity into a dark age. Instead mobs consisting of the original survivors of the war formed in protest to the technology and culture they blamed for bringing about the war. These people, known as 'Simpletons' began burning books in mass and toppling the remnants of pre-war governments around the world in order to 'start again'. Leibowitz took upon himself the task of protecting books during this period and learning how to copy them by hand and memory after joining the Catholic clergy. His efforts at preserving the faith and Human knowledge lead to him being canonized under the Pope of New Rome (St. Louis) in the 26th century (2501-2600). The Order of St. Leibowitz exists in After the End.
Numerous character in the game speculate about the Event. Those speculations include the sea boiling and asphyxiating humanity, women going barren and causing a massive drop in human population, or a man-made catastrophe that exterminated global population.
The decline theory
It is possible that the event was not a single devastating event, instead being a slow process that ended human civilization. According to this theory, a combination of oil scarcity and mankind not developing renewable energies would have made intercontinental trade impossible, which would have made it impossible for pre-event people to keep their lifestyle. Eventually long distance communication would have ended entirely, modern technology would've been forgotten, cities would have been abandoned and governments would have collapsed or lost control over most of their territory (which seems to be Mexico's case, where the capital is controlled by Mexico but most of the country is controlled by independent states).
- The Event was purposely left unclear, to allow players to reach their own conclusion.