One of the reasons for the decline of the Ainu population in the Ezo area during the late Edo period, or the early 19th century, is reported to have been a smallpox epidemic introduced through ships engaged in maritime trade. It was the custom of the Ainu to flee to the mountains during outbreaks of smallpox and other infectious diseases. Here, I would like to introduce the countermeasures implemented by the Matsumae domain and the Edo shogunate to control the spread of infections in Ezo. Learning about containment strategies from that period could prove beneficial for today’s Japan as the number of COVID-19 cases continues to rise.