AbstractThe development and expansion of 20th-century urbanization have led to large-scale populated regions that did not exist prior to this era. City-region is a kind of 20-century large-scale concept recognized as the most advanced stage of urban development. Regardless of its long history, the concept of city-region does not enjoy a standard definition. In this vein, the present paper seeks to provide a suitable framework for the primary argument determining the city-region boundary. Indeed, understanding the boundary allows planners to study a precise area, resulting in refining the concept and meticulously planning. Therefore, as applied research, it is aimed to respond to the practical problem in spatial planning by expanding and developing the city-region’s knowledge base. The paper has a mixed-method, using content analysis, the Structural Equation Model techniques, and Hot spot analysis. The results introduce six factors for determining the city-region’s boundary, including economic self-sufficiency, community relation, regional competitiveness, balanced management, services and infrastructure capacities, and the space of flows. The research’s flexible model allows planners to adjust it based on their field of study, inferring that the proposed model is utterly comprehensive; however, having access to different databases, scholars may encounter a challenge to adapt indicators. Accordingly, indicators should be customized based on general ones. In this study, the indicators are customized according to Iran’s data sources, and the output framework is tested on the Tehran region that deals with inefficiencies in urban and regional planning.