Wetlands serve a critical function in water storage and ecological diversity maintenance. However, human activities have resulted in wetland loss in the middle and lower reaches of the Yangtze River Basin (MLYRB), while the wetland distribution in this area shows great discrepancy in previous estimates. It is, therefore, imperative to estimate the distribution of potential wetlands at present and project their variation under future climate change scenarios. In this study, we simulate the wetland distribution in the MLYRB at 15″ resolution using 5 machine learning methods with 19 predicting factors of topographic index, vegetation index, climate data, hydrological data, and soil type data. A 5-fold cross-validation with observed permanent wetlands shows that the reconstructions from Adaptive Boosting tree (AdaBoost) algorithm have the highest accuracy of 97.5%. The potential wetland area in the MLYRB is approximately ~1.25 × 105 km2, accounting for 15.66% of the study region. Direct human activities have led to the loss of nearly half of the potential wetlands. Furthermore, sensitivity experiments with the well-trained models are performed to quantify the response of the total wetland area to each influencing factor. Results indicate vulnerability of wetland areas to increases in leaf area index (LAI), coldest season temperature, warmest season temperature, and solar radiation. By the 2100s, the potential wetland area is expected to decrease by 40.5% and 50.6% under the intermediate and very high emissions scenarios, respectively. The changes in LAI and the coldest season temperature will contribute to 50% and 40% of this loss of potential wetlands, respectively. Wetland loss may further undermine biodiversity, such as waterfowl, and fail to provide functions such as flood protection, and water supply. This work reveals the spatial pattern of potential wetland areas and their sensitivity to climate changes, stressing the need for effective strategies to mitigate wetland loss at specific regions in the MLYRB.