Abstract: In order to explore future runoff changes in the Heihe and Baihe River Basins in the source region of the Yellow River, and to provide a reference for water resource management and decision-making in these basins, the changes in runoff at the hydrological stations in the Heihe and Baihe River Basins are simulated, projected, and analyzed based on the SWAT hydrological model by using the MPI-ESM1-2-HR climate model of the Coupled Model Intercomparison Project Phase 6 (CMIP6). The results show that: (1) Based on the MPI-ESM1-2-HR climate model, the average annual runoff of Ruoergai and Tangke stations shows an overall increasing trend under the SSP1-2.6 scenario, while the average annual runoff of Ruoergai and Tangke stations shows an overall decreasing trend under the SSP4-4.5, SSP3-7.0, and SSP5-8.5 scenarios. (2) Compared with the baseline period (1981—2010), the average annual runoff of Ruoergai and Tangke stations shows an increasing trend under the four scenarios from 2021 to 2050. (3) Under the SSP1-2.6 scenario, the annual variation of runoff at Ruoergai Station during different periods is similar to the baseline period (all concentrated from May to September). Under the SSP2-4.5 and SSP3-7.0 scenarios, the annual variation of runoff at Ruoergai from 2021 to 2050 follows a single peak curve consistent with the baseline period, while the annual variation trend of runoff in Ruoergai from 2051—2080 and 2081—2100 shows a bimodal characteristic. Under the SSP5-8.5 scenario, the annual variation of Ruoergai runoff from 2021 to 2050 is basically consistent with the baseline period. (4) Under the SSP1-2.6 and SSP2-4.5 scenarios, the annual runoff variation trends at Tangke Station during different future periods are generally consistent. Under the SSP3-7.0 and SSP5-8.5 scenarios, the runoff variation trends from June to December at Tangke Station during different future periods are relatively consistent with the baseline period, while those in the remaining months show certain differences compared with the baseline period.