Madhava Nidana is an authentic and popular Ayurvedic text written by Madhavakara (700–800 AD). Masurika has been well correlated with smallpox, and Madhavakara was the first author to give an independent disease status along with a detailed description of Masurika in Masurika Nidana chapter of the Madhava Nidana. Published literature on Masurika is scarce, and the present review is focused on exploring the contents of Masurika Nidana chapter of Madhava Nidana and its similarity with smallpox. Concepts of nutritional immunology with special reference to the complex interactions between diet, immune status and susceptibility to viral infections can be found in the Masurika Nidana chapter. Krura Grahekshanat Deshe denotes epidemics or pandemics caused by pox viruses. There is a profound similarity between the description of Masurika and smallpox among various domains such as clinical features, types, morphological characteristics of skin lesions, prognosis, and complications. Bhramareneva Viddhani Kurvanti Astheeni (i.e., osteomyelitis variolosa) may denote the findings of postmortem examination or autopsy findings of smallpox patients done by Madhavakara. Although smallpox has been eradicated, the present study findings may provide important information regarding the diagnostic possibilities and management guidelines of other pox virus diseases or other viral epidemics that are associated with skin eruptions.