The evaluation of the railway operation safety situation is important for managers to ensure transportation safety and make control decisions. In this study, first, six situation indicators are designed from a regional perspective based on the characteristics of railway operation accidents, and the quantitative methods of these indicators are determined. Second, an improved technique for order of preference by similarity to ideal solution (TOPSIS) method is developed to evaluate the railway operation safety situation against the situation indicators. Based on the set-pair analysis (SPA) theory and cosine similarity measure (CSM), the comprehensive evaluation values and rankings of the safety situation are first calculated from the distance and trend levels for each period. Game theory is then employed to determine a more reasonable combined weight, and the values of the parameters involved in the situation indicators are also estimated. The real-life statistical accident data in a regional area of China from 2016 to 2018 are chosen as a case study to verify the proposed method. A brief analysis is conducted, resulting in suggestions for the evaluation results. Two groups of comparative experiments are designed to demonstrate the feasibility and effectiveness of the method. Finally, the quality of the evaluation results is verified through actual conditions and expert scoring. Some extensions and potential practical applications of this work are discussed.