A rural settlement is a socio-ecological system (SES) characterized by multiple systemic attributes, including natural, socio-economic, morphological, and locational elements. However, only a few previous studies have quantitatively revealed the complex relationships among subsystems of rural socio-ecological systems (RSES). With a systems-oriented perspective, this study constructed an ontological framework for better understanding the complex inter- and intra-relationships in Chinese rural settlements. A quantitative structural equation modeling method was adopted to explore the interactions of the internal and external subsystems of RSES. Analysis of the RSES in Guangdong Province indicated that: (a) the natural subsystem provided the primary material conditions for forming and developing the rural settlement’s morphological and socio-economic subsystems. The relationship between morphological and socio-economic subsystems was reciprocal, and the positive effect brought by socio-economic development could be the main driving force for the morphological evolution in rural settlements; (b) locational conditions served as bridges between the internal and external systems so that the external system could dramatically change the rural settlement through nearby economic and social activities; and (c) the systemic perspective could be a promising approach to coordinate natural environments, bottom-up rural economic vitality and the planning guidance of the government, promoting the rural revitalization and sustainable development in developing countries.