Soil salinization is a serious global issue; by 2050, without intervention, 50% of the cultivated land area will be affected by salinization. Therefore, estimating and predicting future soil salinity is crucial for preventing soil salinization and investigating potential arable land resources. In this study, several machine learning methods (random forest (RF), Light Gradient Boosting Machine (LightGBM), Gradient Boosting Decision Tree (GBDT), and eXtreme Gradient Boosting (XGBoost)) were used to estimate the soil salinity in the Werigan–Kuqa River Delta Oasis region of China from 2001 to 2021. The cellular automata (CA)–Markov model was used to predict soil salinity types from 2020 to 2050. The LightGBM method exhibited the highest accuracy, and the overall prediction accuracy of the methods had the following order: LightGBM > RF > GBRT > XGBoost. Moderately saline, severely saline, and saline soils were dominant in the east and south of the research area, while non-saline and mildly saline soils were widely distributed in the inner oasis area. A marked decreasing trend in the soil salt content was observed from 2001 to 2021, with a decreasing rate of 4.28 g/kg·10 a−1. The primary change included the conversion of mildly and severely saline soil types to non-saline soil. The generalized difference vegetation index (51%), Bio (30%), and temperature vegetation drought index (27%) had the greatest influence, followed by variables associated with soil attributes (soil organic carbon and soil organic carbon stock) and terrain (topographic wetness index, slope, aspect, curvature, and topographic relief index). Overall, the CA–Markov simulation resulted exhibited suitable accuracy (kappa = 0.6736). Furthermore, areas with non-saline and mildly saline soils will increase while areas with other salinity levels will continue to decrease from 2020 to 2050. From 2046 to 2050, numerous areas with saline soil will be converted to non-saline soil. These results can provide support for salinization control, agricultural production, and soil investigations in the future. The gradual decline in soil salinization in the research area in the past 20 years may have resulted from large-scale land reclamation, which has turned saline alkali land into arable land and is also related to effective measures taken by the local government to control salinization.