The re-emergence of infectious diseases has been a rampant public health challenge in Kerala over the past few decades with high rates of mortality and morbidity. Against this backdrop, this study explored the ensuing and transforming vulnerabilities it posed on poor and marginalised communities and the governance response adopted by the state’s decentralised health systems. In terms of vulnerability, we explored the morbidity patterns, illness response and magnitude of out-of-pocket (OOP) health expenditure associated with these illnesses. The governance response was examined through the capacity of the decentralised system to assess and manage the risk, and its ability to harness community participation in the process. The study employed a mixed methodology including a cross-sectional survey of 430 sick respondents and 30 in-depth qualitative interviews. A mixed-method study was designed to understand how individual attributes mediate structural processes to define health outcomes. Individuals from various socio-spatial locations, having one or more cases of selected re-emerging infectious diseases (Chikungunya, Dengue, Malaria and Leptospirosis) within a reference period of three months were included in the study. The findings demonstrated that vulnerabilities associated with these diseases are jointly determined by individual, household and health system factors. The study detailed how these factors have interacted and intersected at varying points to create and reinforce multiple layers of vulnerability. The results illustrated the irreplaceability of the state in addressing the health needs of its population, especially in the context of emerging pandemics like Covid-19 and raised questions regarding the restructuring of health systems in the changing epidemiological and public health governance contexts to enhance its responsiveness and efficacy.