Under the background of climate change, long-term trends in atmospheric-marine processes have been observed over the past decades. Being a subtropical estuary influenced by East Asian monsoon wind, the Pearl River Estuary (PRE) is chosen as a prototype to investigate the response of estuarine hydrodynamics to the local climatic regime shift in wind forcing. Analyses from ERA5 wind data and local meteorological observations have revealed that summer wind over PRE (prevailed by the up-estuary wind) was decreasing in magnitude and shifting anticlockwise from southwesterly to southeasterly over the past 42 years (1979–2020). Using a fully calibrated three-dimensional numerical model, the hydrodynamic circulation of PRE were simulated for 42 years with realistic daily wind forcing and repeated annual cycles for other forcing fields. Both the least-squares fitting and the EOF analysis demonstrate that the summertime longitudinal flow was strengthened while the lateral circulation was weakened over the past 42 years. Comparative analyses of the results obtained from the process-oriented numerical experiments revealed that the decreasing wind speed is the dominant factor for the strengthening of the longitudinal circulation, while the shifting wind direction is the dominant factor for the weakening of the lateral circulation. Using calculated long-term trends in wind forcing, wind conditions are predicted for 2100. The model results indicate that by 2100, there will be a further strengthening of the longitudinal circulation and a further weakening of the lateral circulation during the summer. The momentum budget reveals that the baroclinic pressure gradient and the diffusion term are the dominant terms modulating the changes of hydrodynamic circulation. The water mass in the PRE will become saltier, and the exchange between the deep channel and shallow shoals of the estuary will be slowed down in the future. The impact of these changes on brackish water habitats and local ecosystems needs further study.