The Black Death reached Hungary in 1349. The first wave of the epidemic ended in June, but it returned in September, killing Louis's first wife, Margaret. Louis also fell ill, but survived the plague.

Although the Black Death was less devastating in the sparsely populated Hungary than in other parts of Europe, there were regions that became depopulated in 1349, and the demand for work force increased in the subsequent years. Indeed, colonization also continued in the 14th century. The new settlers mainly came from Moravia, Poland and other neighboring countries.