While they are important, local or catchment-level conservation efforts are by themselves unlikely to bend the curve of dramatic global-scale biodiversity loss in rivers, lakes, and freshwater wetlands. Other interventions will also be required, especially those that address the underlying socio-economic drivers of freshwater ecosystem degradation. Such drivers often manifest through decisions made at national or international scales by policymakers and business leaders in sectors including water resource management, agriculture and food production, energy generation, and inland fisheries. Few analyses have traced the impacts of such decisions on freshwater ecosystems and biodiversity, and the evidence base provides scant insight into effective approaches for addressing these underlying drivers. We begin to address this strategic knowledge gap by describing key policy and business sectors that the conservation and science communities should engage to address the systemic drivers of global freshwater biodiversity loss. Drawing on diverse experiences of international policy and business discourses and applied freshwater sciences, we provide an overview of international sector-specific risks and opportunities for freshwater conservation and propose potential priorities for engagement. We reflect on actions the freshwater sciences community can take to respond to these risks and opportunities, and we suggest priorities to shape a more systemic, driver-focused approach to freshwater conservation research that can support the integration of freshwater biodiversity considerations into policy and business decisions.