Abstract: In response to the risk of ecosystem service function degradation under the background of rapid urbanization in Guangdong Province, this study evaluates the spatiotemporal evolution of ecosystem service value (ESV) from 2001 to 2021 based on land-use change data using the equivalent factor method, and further analyzes the driving factors of its spatial differentiation with the geographic detector model. The results show that: 1) during the study period, construction land expanded significantly, forestland slightly increased, while cropland, water bodies, and grassland all declined to varying degrees. Overall, the land-use dynamic degree showed a downward trend, accompanied by large-scale transfers among different land-use types. 2) The total ESV in Guangdong decreased from approximately 1038.51 billion yuan in 2001 to about 981.65 billion yuan in 2021, a reduction of around 56.87 billion yuan. Among all land-use types, forestland contributed the most to the ESV change and played a key role in maintaining regional ecological balance. Spatially, ESV presented a “high in the north, low in the south” pattern. 3) The spatial differentiation of ESV was jointly influenced by natural and socio-economic factors, among which the Human Activity Index (HAI) had the highest explanatory power. Slope, elevation, NDVI, temperature, population density, road density, and GDP were also important factors, while the interaction between road density and slope exerted the most significant influence on ESV. The findings provide quantitative evidence and scientific support for improving regional ecological environment quality, constructing an ecological security pattern, and promoting the coordinated development of human–environment relationships.