Healthcare is a major emitter of environmental pollutants that adversely affect health. Within the healthcare community, awareness of these effects is low, and recognition of the duty to address them is only beginning to gain traction. Healthcare sustainability science explores dimensions of resource consumption and environmental emissions associated with healthcare activities. This emerging field provides tools and metrics to quantify the unintended consequences of healthcare delivery and evaluate effective approaches that improve patient safety while protecting public health. This narrative review describes the scope of healthcare sustainability research, identifies knowledge gaps, introduces a framework for applications of existing research methods and tools to the healthcare context, and establishes research priorities to improve the environmental performance of healthcare services. The framework was developed through review of the current state of healthcare sustainability science and expert consensus by the Working Group for Environmental Sustainability in Clinical Care. Key recommendations include: development of a comprehensive life cycle inventory database for medical devices and drugs; application of standardized sustainability performance metrics for clinician, hospital/health system, and national levels; revision of infection control standards driving non-evidence-based uptake of single-use disposable devices; call for increased federal research funding; and formation of a Global Commission on the Advancement of Environmental Sustainability in Healthcare. There is urgent need for research that informs policy and practice to address the public health crisis arising from healthcare pollution. A transformational vision is required to align research priorities to achieve a sustainable healthcare system that advances quality, safety and value.