The Plague of Justinian was caused by the Bubonic plague. It ran from 541–549 and may have killed one hundred million. It killed 25–60% of European population.
In terms of death toll, it is akin to the Spanish Flu (1918-20), which also killed up to 100 million (albeit of a larger world population).
In terms of death toll, the third placed pandemic is the HIV-AIDS pandemic. It reached 45 million in 2026, but with Trump's destruction of USAID, the body critical to providing treatment in Africa, the number is likely to increase sharply again after years in decline.
In fourth place was the Black Death which is believed to have killed 25–50 million - again from a smaller world population. It ran from 1346–1353.
In fifth place is the covid pandemic, with an estimated 38 million to date. Vaccines thankfully prevented it reaching numbers akin to the Spanish Flu - something it had the potential to do. However it is by no means over, and there remains the risk of a variant appearing that current vaccines cannot control.
The Cocoliztli epidemic of 1545–1548 was limited to Mexico, but is thought to have killed up to 80% of the population.
Knowing how many died is not always easy. Sometimes a person technically died of something else, but would have survived but for being ill with the pandemic. Other times record-keeping collapses due to mass deaths so the total number who died is unknown. That is the case in some US cities in the Spanish Flu. Death certification, burial records, church records, etc all broke down as those who had kept them died or were too ill. Bodies in Philadelphia were buried in mass graves without counting numbers as there were so many rotting bodies needing burial they had not time to count the dead. Some people died in their homes, but the collapse in the collection of corpses forced families to dump the bodies of the dead in back lanes as the smell of the decaying corpse in the house was unbearable. It would disappear but they would not know had it been picked up for burial in mass graves, or simply eaten by rats, dogs and cats. So in pandemics often all that can be made are estimates.
When research is done afterwards, it always turns out that the estimates were a considerable under-estimate. Bodies buried in the Spanish Flu in Greenland and the Artic were exhumed some years ago. They had remained undecayed in the frozen earth. When autopsies were done, it was found that many people whose deaths were originally thought to have been caused by something else had been caused by the Spanish Flu. Detailed exhumations over the decades has led to the conclusion that the original presumption that 50 million died was a considerable under-estimation, and the number was potentially one hundred million.
Overall, pandemics are a constant regular occurrence. The best way to stop its spread is use lockdowns - something learned in the 14th century. Most pandemics are spread by person-to-person. Therefore to break the transmission, lockdowns have to happen to stop people becoming in contact with someone with it. Thankfully, we can develop vaccines, and once a vaccine achieves the right number, lockdowns can be eased and ended. Lockdowns feature in plays, poems and art from the Middle Ages. A lockdown is critical in Shakespeare's Romeo and Juliet. It is why a vital message to Romeo cannot be passed on - the city he is in is in lockdown and the gates are locked, so no-one can enter.
We even know throughout history that churches and ale-houses/pubs are the most dangerous places. People remain in the same spot and get infected in churches. In pubs, alcohol dims awareness of distancing. So right back to the middle ages, both have to be shut. It is nothing new. In contrast, modern supermarkets are not dangerous. Everyone is on the move. They have air-conditioning and aisles are wide. So people may only come close to an infected person for a split second. In a church, with everyone sitting, standing and kneeling at the same spot for half an hour or more, they are likely to get the infection if they are near someone carrying the virus.
Pandemics are as certain as night and day. The only thing we don't know is when they will hit. One might not hit for fifty years, or it could hit next month. The usual cause is the same - some animal virus jumps species into a human, then spreads. The Spanish Flu is suspected of moving from a pig to the farm worker looking after it. He had arranged to join the army as the US was in WWI, went to the local army fort and unbeknown to him spread it to soldiers, who spread it through the army and brought it to Europe. They infected workers at the port of Brest. They infected crew on merchant ships who brought it to their own countries. And all from an apparent farm worker on a farm in Kansas nursing a sick pig.
