Guizhou, China, is known for the abundance of subterranean drainage systems with sinkholes. Sinkholes may develop when acidic water starts to dissolve the surface of bedrock or bedding planes. The dissolution characteristics of limestone play a crucial role in the development of sinkholes. The main objective of this study was to develop a quantitative tool for evaluating the dissolution ability for sinkhole formations in the karst regions of Guizhou. The present study investigates a number of properties of limestone that may influence the dissolution in the karst regions of Guizhou. Over 200 rock samples were collected and tested to determine the CaO/MgO ratio, clast content, clastic/matrix ratio, primary porosity, permeability, and fracture density. A quantitative approach was developed to synthesize the influences of these multiple factors to establish the order of the limestone solubility in different regions of Guizhou via numerical modeling using the analytical hierarchy process (AHP) theory. It was found that the solubility of the karstic limestone from different geological formations was in the following descending order: Carboniferous Huanglong-Maping Formation, Permian Qixia-Maokou Formation, Cambrian Qingxudong Formation, and Triassic Yongningzhen Formation. As the water-bearing capacity of the geological formations in these regions is closely associated with underground cavern and sinkhole formations, the approach explored in the present study may have strong implications for the exploration and utilization of karst groundwater resources.