Extensive soil and water conservation practices have profoundly reshaped sediment transport in the middle reaches of the Yellow River. Scientifically quantifying the driving factors behind these changes is essential for effective watershed management. Previous studies have primarily focused on the direct contributions of climate and human activities to sediment load across the entire watershed, often neglecting runoff-mediated pathways and spatial heterogeneity. This study analyzed the spatiotemporal variation in sediment load across the middle Yellow River and its sub-regions using continuous hydrological records from 1960 to 2020. Partial Least Squares Structural Equation Modeling was applied to elucidate the direct effects of vegetation and climate on sediment load from runoff-mediated indirect effects and to reveal the spatial heterogeneity of driving factors. Results showed a highly significant decline in sediment load (P < 0.01) from 1960 to 2020. Since 2000, Wu-Long region has become the main sediment source. The driving factors of sediment load in the study area exhibited both temporal and spatial variability. Temporally, climate prevailed from 1980 to 1999 (total effect = 0.37), whereas vegetation became dominant from 2000 to 2020 (total effect = -0.33). Spatially, Tou-Wu region was primarily influenced by climate (-0.85 <= total effect <= -0.52), while vegetation dominated the Wu-Long region (-0.41 <= total effect <= 0.57). Runoff had a highly significant effect on sediment load variations (P < 0.01). The indirect effects of vegetation through runoff in the Tou-Long and Wu-Long regions (-0.55 to 0.36 and -0.59 to 0.32, respectively) exceeded the direct effects (-0.10 to 0.10 and 0.18 to 0.25), confirming runoff as a key mediating factor. This study reveals spatial heterogeneity of sediment load drivers in the Hekou-Longmen region, providing a scientific basis for precision management and sustainable ecology in the middle Yellow River.