Southeast Asia, characterized by its tropical climate, rapid socio-economic development, urbanization, and shifting environmental dynamics, is increasingly recognizing health issues as pivotal threats to regional security. This region stands as a focal point for public health emergencies, with elevated risks of emerging infectious diseases and some of the highest global mortality rates, primarily attributed to disasters. Additionally, Southeast Asia is undergoing the global epidemiological transition from infectious diseases to noncommunicable diseases (NCDs), including cardiovascular diseases and stroke. These challenges are exacerbated by the escalating consequences of climate change. This study finds that the profound impact of health on regional security cannot be underestimated, given its enduring socio-economic repercussions. ASEAN countries collectively incurred staggering economic losses of US$91 billion due to disaster-related events during the period of 2004-2014. Similarly, NCDs and infectious diseases have become substantial economic burdens, often resulting in out-of-pocket medical expenses, intangible caregiver burdens, and long-term productivity declines. The unprecedented economic toll of the COVID-19 pandemic, driven by public health responses, border closures, and travel restrictions, further underscores the intricate relationship between health and security. Against this complex backdrop, the concept of health security, defined as “the measures required to minimize vulnerability to public health events that transcend borders,” emerges as a critical imperative for safeguarding ASEAN’s security. Achieving this necessitates the establishment of a resilient, secure, and sustainable regional health architecture that can effectively respond to current and emerging health challenges while promoting long-term regional stability and prosperity.