Karst areas are characterized by poor surface water storage capacity, which makes them more sensitive to drought events. To enhance drought resistance in karst landform areas, this study focuses on a typical region in the Yun–Gui Plateau of China, specifically Guizhou Province, which includes 88 counties and districts. According to the regional characteristics, the index system for the assessment of drought resistance and disaster reduction ability was constructed to include 17 indexes in five evaluation layers, including natural conditions, water conservancy project, economic strength, water usage and water conservation level, and emergency support capacity. A comprehensive evaluation was conducted using a fuzzy evaluation model. Furthermore, the drought resistance and disaster reduction capacity of Guizhou Province was evaluated according to the fulfillment of water supply and water demand under the frequency of 75%, 90%, 95%, 97%, and 99% drought frequency inflow in each research unit. This assessment serves to define the spatial distribution pattern of drought resistance and disaster reduction capability within the province. Additionally, according to the results of the supply–demand balance method, the weight of the main influencing factors in regards to drought resistance and disaster reduction ability was optimized and adjusted to identify the key restricting factors of drought resistance and disaster reduction ability. This research data was obtained from the National Disaster Survey database, aiming to provide practical guidance for drought resistance in Guizhou Province. The research findings show that: (1) the distribution characteristics of drought resistance and disaster reduction capability in Guizhou Province are the most significant in Guiyang City, Liupanshui City, and Anshun City in the southwest, with higher drought resistance and disaster reduction ability found in central region, and lower drought resistance primarily identified in the eastern part of Qiandongnan Prefecture, Tongren City, the southern part of Qiannan Prefecture, and the northwestern part of Bijie City; (2) there are six main influencing factors in the three criterion layers, i.e., hydraulic engineering, emergency drought resistance, and social economy, and their contribution rates are as follows: surface water supply and storage rate > average number of soil moisture monitoring stations > per capita GDP > agricultural emergency drought irrigation rate > regional water supply assurance rate > cultivated land effective irrigation rate.