The Amazon River Basin’s extraordinary social–ecological system is sustained by various water phases, fluxes, and stores that are interconnected across the tropical Andes mountains, Amazon lowlands, and Atlantic Ocean. This “Andes–Amazon–Atlantic” (AAA) pathway is a complex hydroclimatic system linked by the regional water cycle through atmospheric circulation and continental hydrology. Here, we aim to articulate the AAA hydroclimate pathway as a foundational system for research, management, conservation, and governance of aquatic systems of the Amazon Basin. We identify and describe the AAA pathway as an interdependent, multidirectional, and multiscale hydroclimate system. We then present an assessment of recent (1981 to 2020) changes in the AAA pathway, primarily reflecting an acceleration in the rates of hydrologic fluxes (i.e., water cycle intensification). We discuss how the changing AAA pathway orchestrates and impacts social–ecological systems. We conclude with four recommendations for the sustainability of the AAA pathway in ongoing research, management, conservation, and governance.