The constant conflict between the rapidly developing socioeconomic and ecological environment within the Guangdong–Hong Kong–Macao Greater Bay Area necessitates the exploration of ecosystem vulnerability patterns and driving mechanisms. A comprehensive social–economic–ecological framework is proposed to assess the ecosystem vulnerability pattern of the Greater Bay Area, specifically spanning from 1990 to 2020. Employing geographic detectors and weighting methods, the study quantifies spatiotemporal variation and the underlying mechanisms driving vulnerability in the study area. The results demonstrate an obvious trend in ecosystem vulnerability index (ESVI) across the Greater Bay Area, with an initial decline followed by gradual increase during the1990–2020. A substantial majority of the region (approximately 63.85% of the total area) experienced a decline in ESVI from 1990 to 2010. Moreover, the spatial distribution of this decline exhibited a prevailing east-to-west pattern, indicating an overall southward shift over time. Furthermore, a decline was primarily concentrated in the central region and the rapidly expanding urban areas situated on both sides of the Pearl River estuary. Encouragingly, a notable amplification in ESVI was observed between 2010 and 2020, which is attributed to the development, utilization, and protection of land, forests, water bodies, and other pertinent factors associated with urban expansion. The impact of climate change on ESVI changes exhibits a growing magnitude over time, while human activities persist as the predominant driver of ESVI changes. The natural factors exerted a substantial impact on ESVI changes primarily in the upper reaches of the Pearl River, which included topographic relief, precipitation, water network density, biological abundance, and related aspects. Conversely, the pronounced influence of human activities on ESVI changes predominantly manifests within the urban agglomeration of the Pearl River Delta. Key contributors to such a manifestation encompass land change types, intensity of human activities, population density, and related variables. Changes in land use have the potential to induce heightened ecological vulnerability changes. The amelioration of ecological protection and land use practices can be mitigated and reduced by employing ESVI. Moreover, the framework introduced in this study holds the potential to extend vulnerability assessments to other regions with similar ecosystem types. It is expected that the findings derived from this framework could contribute to the formulation of policy recommendations pertaining to ecosystem protection and management.