Infrastructures such as energy, transport, water, waste, and telecommunications are essential to the sustainability, social wellbeing and economic prosperity of nations. In meeting future infrastructure needs of a growing global population there is a need for creating resilient infrastructures, which can withstand large human-induced or natural shocks. Understanding systemic vulnerabilities and risks to infrastructures goes a long way in meeting such challenges. There is a general lack of models and tools that provide such understanding in an easily interpretable and usable way. The paper “System-of-systems framework for global infrastructure vulnerability assessments” addresses the need for a system-of-systems framework that applies to assess infrastructure vulnerabilities in a generalized sense. The system-of-systems framework present here outlines basic models and information on: (1) spatial hazards; (2) interdependent spatial infrastructure network assembly; (3) infrastructure customer service disruption; (4) macroeconomic loss estimation; and (5) simulation and generation of spatial vulnerability outcomes. The paper’s aim is to create individual models and a coherent framework for regional or national scale vulnerability assessment that is replicable to multiple contexts globally. This builds on previous studies developed for different infrastructure risk assessments for United Kingdom, China, and New Zealand. The paper presents a demonstration of the framework for a case-study of the Gaza Strip, to show how electricity infrastructure failures induce direct and indirect vulnerabilities on dependent energy, water, waste water, health, banking, and education systems. The results highlight system-wide impacts of individual asset failures and concentrations of spatial vulnerabilities. Such knowledge helps in prioritising national-scale infrastructure risk management and resilience planning. The authors’ aim is to apply such analyses to inform mitigation and adaptation challenges for developed and developing world contexts around the world.