The global health system (GHS) is ill-equipped to deal with the increasing number of transnational challenges. The GHS needs reform to enhance global resilience to future risks to health. In this article we argue that the starting point for any reform must be conceptualizing and studying the GHS as a complex adaptive system (CAS) with a large and escalating number of interconnected global health actors that learn and adapt their behaviours in response to each other and changes in their environment. The GHS can be viewed as a multi-scalar, nested health system comprising all national health systems together with the global health architecture, in which behaviours are influenced by cross-scale interactions. However, current methods cannot adequately capture the dynamism or complexity of the GHS or quantify the effects of challenges or potential reform options. We provide an overview of a selection of systems thinking and complexity science methods available to researchers and highlight the numerous policy insights their application could yield. We also discuss the challenges for researchers of applying these methods and for policy makers of digesting and acting upon them. We encourage application of a CAS approach to GHS research and policy making to help bolster resilience to future risks that transcend national boundaries and system scales.