The construction of desert railways inevitably destructs the environment and aggravates the wind–sand damage along the line. A reasonable railway route is an effective measure to avoid blown sand hazards, save construction costs, and reduce environmental damage. Currently, the selection methods for the railway route scheme are to analyze the qualitative indicators and quantitative indicators separately, and there are few decision-making models for the desert railway scheme. Therefore, this study aims to propose a comprehensive quantitative optimization model of the route scheme for the desert railway. Based on the design principles of hazard reduction, the evaluation index system of the desert railway route is first constructed, including railway design factors, wind-blown sand hazard factors, environmental impact factors, and operation condition factors. Subsequently, the subjective weights and objective weights are combined to obtain the comprehensive weights of the index by utilizing the principle of minimum discrimination information. Finally, the interval number is employed to quantify the linguistic fuzzy number of qualitative indicators, and the optimization model of the route scheme for the desert railway is constructed based on the technique for order preference by similarity to an ideal solution (TOPSIS). The model is verified using the Minfeng-Yuhu section in the Hotan–Ruoqiang railway as the case study. The achieved results reveal that this model enhances the accuracy and efficiency of the railway scheme decision-making and provides a theoretical basis for the optimal design and sand damage control of the desert railway.