In the summer of 541 an outbreak reached the Egyptian port of Pelusium and travelled along with grain ships to Alexandria, then to the coasts of Palestine and Syria, and in the spring of 542 to the capital Constantinople. The contemporary historian Procopius — who saw the epidemic in the city himself — writes that at its peak more than five thousand died each day, with bodies that could not be buried piled into the towers across the Golden Horn. Those figures may be exaggerated, but modern archaeology and ancient-DNA studies have confirmed that the pathogen was the same Yersinia pestis that causes plague today.

The origin is debated; the most likely explanation is that the bacterium reached the Mediterranean basin from rodent reservoirs in Central Asia or East Africa via Red Sea trade routes. Once it arrived on the coasts, in both bubonic (lymph-node swelling) and the more lethal septicaemic forms, it travelled rapidly between cities connected by sea. The same wave reached Gaul, North Africa, Italy and the Iberian peninsula; further waves recurred for about a hundred and fifty years, into the mid-eighth century.

The overall death toll is contested. Older estimates suggested losses approaching half of the Mediterranean population; a revisionist view drawing on work of the last twenty years — Lee Mordechai and colleagues — argues that the evidence from records, grain prices and mass-burial archaeology does not support so dramatic a collapse, and that the effect varied sharply by region. All scholars agree, however, that the Eastern Roman state suffered serious losses of soldiers, taxpayers and farmers.

The effect on imperial politics was indirect but decisive: through the 540s Justinian struggled to hold the territories Belisarius and Narses had won in Italy and North Africa, and within a generation the Lombards took half of Italy. The plague's long shadow is often invoked in arguments about why Byzantium and the Sasanians were so weak in the face of the Arab conquests of the 630s — the evidence is not conclusive, but it is possible to trace the plague through the transition from Late Antiquity to the Early Middle Ages.