The South-to-North Water Diversion Project (SNWDP) is one of the largest cross-basin and cross-region water transfer projects in the world. The Danjiangkou reservoir area, a haven of diverse species, serves as a core water source for the Central Line of the SNWDP. Yet, less research has been conducted on changes in land use and ecosystem services (ESs) in the Danjiangkou reservoir area in the context of the implementation of the SNWDP and other national projects. In this study, we aim to reveal evolutions of land uses and ESs in the Danjiangkou reservoir area and the response of ESs to natural and socio-economic factors. This is essential to enhance the regional sustainable management of the Danjiangkou reservoir area. Based on classified land use maps and the InVEST model, we first analyzed the land use changes and evaluated three typical types of ESs (i.e., water yield (WY), carbon storage (CS) and habitat quality (HQ)) in the Danjiangkou reservoir area during 2000 to 2018. Then, we detected the spatial clustering characteristics and tradeoffs and synergistic relationships of multiple ESs through hot spot analysis and correlation analysis. Finally, we adopt the geographical detector model (GDM) to identify key driving factors of ESs changes. The results show that: (1) During 2000–2018, the area of arable land and woodland decreased by 1.65% and 0.8%, respectively, while the proportion of construction land and water area increased by 1.31% and 1.39%, respectively. (2) The greatest decrease was in WY, decreasing by 59%, while the change in HQ was relatively stable, but showed spatial heterogeneity. (3) The northern, southern and western districts of the reservoir area showed mainly synergies among multiple ESs, while other regions showed mainly trade-offs. (4) Road network density, proportion of construction land and normalized difference vegetation index are the leading factors for ESs variations. These findings can provide reference for formulating more reasonable ecological protection strategies, so as to realize the sustainable management of SNWDP and its headwaters region.