Runoff changes directly affects the rational development and utilization of water resources in the basin, and the statistics and simulation of runoff are essential. In order to analyze the uncertainty of runoff simulation under non-uniform hydrological conditions, the lower reaches of the Yellow River are studied. The main influencing factors of runoff in the lower reaches of the Yellow River were determined by grey correlation method, the sliding sample entropy was used to test the hydrological sequence, and the Zhang model was constructed based on the Budyko hypothesis. The results showed that precipitation and temperature are the main factors for runoff generation (γ>0.5). The precipitation and temperature hydrological meteorological time series in the lower Yellow River have undergone major changes around 1990, which destroyed the consistency of hydrological sequences. The Budyko model has a higher simulation accuracy (NSE>0.9), indicating that it can be used in the runoff simulation of the inhomogeneous hydrometeorological sequence in the lower Yellow River.