The changes and prediction of runoff in the upper reaches of the Yellow River under global climate change are one of the hotspots in watershed ecological hydrological research. In 2008—2020, the relationship between runoff and the changes of climate factors in the upper reaches of the Yellow River basin were systematically analyzed with the monitoring data from 48 meteorological stations in the basin and runoff data from the Toudaoguai hydrological station, while a runoff prediction model was also established. The results show that the monthly average temperature, monthly precipitation, and monthly evapotranspiration in a single month do not show a significant interannual variation trend in most months, but the annual average temperature and precipitation significantly increase, while the annual evapotranspiration also shows an upward trend, but the statistics are not significant. The monthly runoff of most single months and annual runoff shows interannual increasing trends significantly. Based on the significant correlations between monthly average temperature, monthly precipitation, and monthly evapotranspiration with monthly runoff, the climate factors-based runoff prediction model for the upper reaches of the Yellow River basin has good prediction performance.