Abstract: Tonle Sap Lake (TSL) is a seasonal floodplain lake in the Mekong River Basin (MRB), and its hydrological dynamics are crucial to the ecological security and water resource regulation of the basin. Aiming at the deficiencies of existing studies in long-term continuous monitoring, fine characterization at the monthly scale, and quantitative analysis of the combined driving effects of natural and human factors, this study integrates multi-source remote sensing data (MODIS, Landsat, and Sentinel-1/2) and constructs a monthly water area time series from 2000 to 2025 based on the Google Earth Engine (GEE) platform. By combining STL decomposition, Mann–Kendall test, inundation frequency analysis, and shoreline advance-retreat analysis, the spatiotemporal evolution characteristics and driving mechanisms of the lake are systematically revealed. The results show that the TSL presents typical seasonal fluctuations driven by monsoons within a year, while it exhibits an extremely significant continuous shrinking trend at the interannual scale. The shrinkage is mainly concentrated in the peripheral floodplain, and the core water area remains relatively stable. Precipitation dominates the intra-annual rhythm and interannual fluctuations, while upstream reservoir regulation, agricultural expansion, and rising temperature jointly serve as the dominant driving forces for the long-term shrinkage, with the superimposed amplification effect in extreme drought years. This study improves the remote sensing monitoring paradigm for hydrological processes of seasonal lakes in cross-border basins, clarifies the synergistic driving mechanism of climate and human activities, and provides scientific support for the coordinated management of the Mekong River water resources, the ecological protection of Tonle Sap Lake, and the sustainable utilization of floodplain areas.