The Lower Mekong Basin (LMB) is a subsidiary region of the Mekong River, with approximately 50 million people directly dependent on the river for livelihood and economic activities. However, communities in the region are increasingly exposed to multiple hazards that have significant direct and indirect impacts on their livelihoods. To implement efficient risk management strategies, it is important to understand the interlinkages between the different dimensions and factors that influence livelihood security and resilience in such communities. Through a literature review and expert workshop, this paper studies the multi-hazard scenario and impacts in the LMB region and the interlinkages between livelihoods and resilience in the LMB communities. The paper consolidates these findings and proposes a localized assessment framework that can be used by stakeholders in decision-making process. Floods and droughts were identified as primary natural hazards, while a multi-hazard assessment highlighted a wide spatial variation in the hazard levels across the region. The primary impacts of such hazards are on the agricultural communities dependent on the basin’s ecosystem and natural resources for their livelihoods. A holistic framework has been proposed to measure the multi-hazard livelihood security and resilience in LMB communities that can be used by government authorities and development partners in planning and implementing mitigation and preparedness activities to manage and reducing the risk of hazards.