The Antonine Plague of AD 165 to 180, also known as the Plague of Galen (after Galen, the Greek physician who described it), was a prolonged and destructive epidemic, which affected the Roman Empire. It was possibly contracted and spread by soldiers who were returning from campaign in the Near East. Scholars generally believed the plague was smallpox, due to the skin eruptions over the entirety of the body which appeared to be red and black (Horgan), although measles has also been suggested, and recent genetic evidence strongly suggests that the most severe form of smallpox arose in Europe much later. As yet, there is no genetic evidence from the Antonine plague.

Ancient sources agree that the plague is likely to have appeared during the Roman siege of the Mesopotamian city of Seleucia in the winter of 165–166, during the Parthian campaign of Lucius Verus. Ammianus Marcellinus reported that the plague spread to Gaul and to the legions along the Rhine. Eutropius stated that a large proportion of the empire's population died from this outbreak. According to the contemporary Roman historian Cassius Dio, the disease broke out again nine years later in 189 AD and caused up to 2,000 deaths a day in the city of Rome, 25% of those who were affected. The total death count has been estimated at 5–10 million, roughly 10% of the population of the empire. The disease was particularly deadly in the cities and within the Roman army.

The Antonine plague occurred during the last years of the Pax Romana, the high point in the influence, territorial control, and population of the Roman Empire. Historians differ in their opinions of the impact of the plague on the empire in the increasingly troubled eras after its appearance. Based on archaeological records, Roman commercial activity in the Indian Ocean extending to the Indian subcontinent and Southeast Asia from ports of Roman Egypt seems to have suffered a major setback after the plague. This disruption likely contributed to a broader economic decline and social instability throughout the empire in the years that followed.

Epidemics were common in the ancient world, but the Antonine plague was the first known pandemic of the Roman Empire. The Antonine plague spread throughout the Roman Empire and infected many millions of people. The pandemic erupted during the last years of what is often considered the "golden age" of Rome during the reign of co-emperor Marcus Aurelius. The Roman Empire at that time had a population estimated at 75 million people. Historians generally agree that the population of the Roman Empire peaked at about the time that the Antonine Plague appeared and, thereafter, the population declined.

The economic prosperity of the Roman Empire notwithstanding, the conditions were propitious for a pandemic. The population was unhealthy. About 20 percent of the population — a large percentage by ancient standards — lived in one of hundreds of cities; Rome, with a population estimated at one million, being the largest. The cities were a "demographic sink" even in the best of times. The death rate exceeded the birth rates and a constant in-migration of new residents was necessary to maintain the urban population. As perhaps more than one-half of children died before reaching adulthood, the average life expectancy at birth was only in the mid-twenties. Dense urban populations and poor sanitation contributed to the dangers of disease. The connectivity by land and sea between the vast territories of the Roman Empire made the transfer of infectious diseases from one region to another easier and more rapid than it was in smaller, more geographically confined societies. Epidemics of infectious diseases in the empire were common, with nine recorded between 43 BC and 148 AD. The rich were not immune to the unhealthy conditions. For example, only two of emperor Marcus Aurelius' fourteen children are known to have reached adulthood.

A good indicator of nutrition and the disease burden is the average height of the population. The conclusion of the study of thousands of skeletons is that the average Roman was shorter in stature than the people of pre-Roman societies of Italy and the post-Roman societies of the Middle Ages. The view of historian Kyle Harper is that "not for the last time in history, a precocious leap forward in social development brought biological reverses". This decline in average height during the Roman era may reflect the stresses of urbanization, warfare, and economic inequality. Despite increasing development, average height did not increase in Europe between 1000 and 1800, while it increased in the 5th and 6th centuries during late antiquity.

The traditional Roman view attributed the cause of the Antonine plague to the violation by the Roman army of a temple in the city of Seleucia during the Parthian campaign of Lucius Verus. The soldiers then carried it back to the Roman Empire from the Parthian Empire in early 166. However, the first documented case of the plague was in Smyrna (in Roman Anatolia) in 165 where the orator Aelius Aristides almost died from the disease. From the east the plague spread westward reaching Rome in 166 and nearly every corner of the empire by 172. The co-emperor Lucius Verus died from the plague in 169 and it ravaged the Roman army.

The plague endured until about 180 and another epidemic, possibly related, is reported by Dio Cassius to have struck the city of Rome in 189. Two thousand people in the city often died on a single day. Whether this new epidemic, or recurrence of the Antonine plague, impacted the empire outside the city of Rome is unknown.