This integrated operational framework provides an overview of the connections between mental health, neurological and substance use (MNS) conditions, and their links to health, well-being and the broader public health and sustainable development agenda. The need for integrated approaches is increasingly recognized as critical to address the complex interactions between mental health, brain health, substance use, and physical health, particularly in light of global threats such as the COVID-19 pandemic. The framework also provides a series of actions for governments and health service planners and advisors to achieve integration across four domains: leadership and governance; care services; promotion and prevention; and health information systems, evidence generation and research.