The central Asian scenario agrees with the first reports of outbreaks in China in the early 1330s. The plague struck the Chinese province of Hubei in 1334. During 1353–54, more widespread disaster occurred. Chinese accounts of this wave of the disease record a spread to eight distinct areas: Hubei, Jiangxi, Shanxi, Hunan, Guangdong, Guangxi, Henan and Suiyuan (a historical Chinese province that now forms part of Hubei and Nei Mongul provinces), throughout the Mongol/Chinese empires. Historian William McNeill noted that voluminous Chinese records on disease and social disruption survive from this period, but that modern scholars in neither the East nor the West have studied these sources in depth.

It appears that movement by the Mongols and merchant caravans inadvertently brought the plague from central Asia to the Middle East and Europe. The plague was reported in the trading cities of Constantinople and Trebizond in 1347. In that same year the Genoese possession of Caffa, a cathedral city and seaport on the Crimean peninsula in modern day Ukraine, came under siege by an army of Crimean Tatar warriors under the command of Janibeg, backed by Venetian forces. Their objective was disruption of a trading empire Genoa had established in Caffa.

In 1347, a terrible sickness began to strike the besieging army. According to accounts, so many died that the survivors had little time to bury them and bodies were stacked like cords of firewood against the city walls. Although the Tatar/Venetian alliance broke off the siege, the disease had already spread to the city.