The Hengjiang River, which flows through Zhaotong City from south to north, has abundant water resources. However, the water resources are unevenly distributed in the river basin, with a large quantity in the north and a small quantity in the south. Based on these characteristics, the runoff of the study area from 1981 to 2010 was simulated with the multiple regression analysis method, according to the observed annual runoff from hydrological stations in the river basin, the atmospheric circulation index, the SST index, and other indices. A runoff prediction model was established to predict the annual runoff over the period from 2011 to 2016. The results show that the prediction accuracy of the main stream control stations was higher than that of the upstream and tributary stations, which was attributed to water conservancy project construction and other human activities. This study suggests that multiple regression analysis is applicable to the runoff prediction for the Hengjiang River Basin, but the prediction results are various in different regions and at different levels, due to the differences in indices and accessibility of relevant parameters.