With the acceleration of global urbanization and the degradation of environmental resources, cities face enormous challenges in sustainable development, which is more pronounced in the Pearl River Delta (PRD) urban agglomeration of China. The influencing factors and countermeasures of the sustainable development of the PRD were identified through an ecological security assessment that was associated with the coupling coordination degree model and the BP-DEMATEL model. Three index systems were established, including socioeconomic indicators, eco-environmental indicators and both kinds of indicators; from the perspective of the ecological security and coordination degree, developing areas have better sustainability performance with a higher ecological security score on these three index systems (0.3909, 0.4210 and 0.3912, respectively). Further influencing indicator analysis suggested that the fundamental indicator that limits the regional sustainability of the PRD is the urban ecological elasticity (the “Prominence” value is 4.4713 and the “Relation” value is 3.3336), as well as driving indicators, including the normalized difference vegetation index, GDP per capita, the population density and pesticide usage per km2 of cultivated area. Therefore, coordinated development among different cities should be considered. Cities with more native environments are vulnerable to external factors, and industrialized cities lack powerful ecological restoration. Ecological restoration and management measures are suggested to provide guidance for urban managers and promote regional sustainable development.