The SWAT model and RegCM3 regional climate model were used to predict the future trend in change of the runoff in the source region of the Yellow River under an A1B scenario. The SWAT model for the source region of the Yellow River was constructed, and it was calibrated and verified with hydrometeorological data, including daily temperature, precipitation, and discharge, from 2000 to 2005 and from 2006 to 2008, respectively. The Nash-Suttcliffe efficiency coefficient was 0. 86 in the calibration period and 0. 89 in the verification period, and the correlation coefficient was 0. 83 in the calibration period and 0. 86 in the verification period, indicating that the model’s simulation effect was good. The RegCM3 regional climate model’s capability of simulating the surface air temperature and the precipitation in the source region of the Yellow River was evaluated, and the simulation results, which agreed with observations, were satisfactory. The climate data of the source region of the Yellow River under the A1B scenario predicted by the RegCM3 regional climate model were processed by the system through correction and interpolation, and then applied to the SWAT model to simulate the runoff series of the source region of the Yellow River from 2010 to 2098 and predict the change trend of runoff in the future. The results show that runoff at the Tangnaihai Station in the source region of the Yellow River will decrease continuously from 2010 to 2098 in general; it will decrease from 2010 to 2039, will increase from 2040 to 2069, and will decrease from 2070 to 2098; during the periods from 2010 to 2039 and from 2040 to 2069, it will change insignificantly; and during the period from 2070 to 2098, it will have a significantly decreasing trend.