The vulnerability of water resources is an important criterion for evaluating the carrying capacity of water resources systems under the influence of climate change and human activities. Moreover, assessment and prediction of river basins’ water resources vulnerability are important means to assess the water resources security state of river basins and identify possible problems in future water resources systems. Based on the constructed indicator system of water resources vulnerability assessment in Song-Liao River Basin, this paper uses the neighborhood rough set (abbreviated as NRS) method to reduce the dimensionality of the original indicator system to remove redundant attributes. Then, assessment indicators’ standard values after dimensionality reduction are taken as the evaluation sample, and the random forest regression (abbreviated as RF) model is used to assess the water resources vulnerability of the river basin. Finally, based on data under three different future climate and socio-economic scenarios, scenario predictions are made on the vulnerability of future water resources. The results show that the overall water resources vulnerability of the Song-Liao River Basin has not improved significantly in the past 18 years, and the overall vulnerability of the Song-Liao River Basin is in the level V of moderate to high vulnerability. In the future scenario 1, the overall water resources vulnerability of the river basin will improve, and it is expected to achieve an improvement to the level III of moderate to low vulnerability. At the same time, the natural vulnerability and vulnerability of carrying capacity will increase significantly in the future, and the man-made vulnerability will increase slowly, which will deteriorate to the level V of moderate to high vulnerability under Scenario 3. Therefore, taking active measures can significantly reduce the vulnerability of nature and carrying capacity, but man-made vulnerability will become a bottleneck restricting the fragility of the overall water resources of the river basin in the future.