The first pandemic of bubonic plague, which struck the Byzantine Empire in 541 CE and recurred across the Mediterranean and Near East for two centuries — killing millions, disrupting Justinian's attempt to reunify the Roman Empire, and establishing plague as the defining catastrophe of the ancient world's final era.
The Black Death of 1347 is famous. The plague that came before it is not. The Justinianic Plague killed as much as a quarter of the eastern Mediterranean's population across two centuries of recurrence — and may have ended the last serious attempt to reunify the Roman Empire. It was the first pandemic, and the world has never fully understood what it produced.