Abstract: Flood regulation service (FRS) stands as one of the key benefits that people get from the ecosystem. Under the influence of climate change and human activities, the relationship between supply and demand of FRS would increasingly affect regional flood risk and sustainable development. However, there was currently a lack of systematic study on the future supply-demand relationship of FRS in the flood-vulnerable area undergoing rapidly development in China. This study integrated the Scenario Model Intercomparison Project (ScenarioMIP) with the Shared Socioeconomic Pathways (SSPs) datasets and climate model data to quantify the supply-demand ratio (SDR) of FRS in the Yangtze River Delta (YRD), China from 2020 to 2050. Trend analyses were conducted using linear regression, Theil-Sen median estimation, and Hurst exponent analysis, while key drivers of SDR changes were identified and quantified through the Lindeman-Merenda-Gold (LMG) method between 2021 and 2050. Results show that the supply of FRS in the YRD was generally insufficient to meet the demand. The imbalanced subbasins covered 88.24% of the total study area, with 34.48% of this imbalanced area concentrated in the Southeastern Basin in China. During 2021 and 2050, the imbalance of FRS supply-demand relationship would largely aggravate in the YRD, of which the aggravated area would account for 77.23%. Under different scenarios, the SDR for FRS would decrease significantly, with rates ranging from –5.45 × 10^–4 to –2.06 × 10^–4 (P < 0.05). Especially, the decline rate of SDR in the YRD Basin (DeltaB) reached 2.92 times that the average of YRD. Human activities were the primary factors that exacerbated the imbalance in FRS supply-demand relationship, of which the relative contribution rate exceeds 75%. Particular attention should be directed toward critical regions like the Southeast Basin in China (SEB) and DeltaB where substantial aggravation of supply-demand imbalances of FRS is projected.