<p>Different iron fractions play critical role in the biogeochemical processes, significantly influencing the cycling of numerous elements. However, the distribution, influencing factors, and relationships between iron fractions, heavy metals, and organic matter in the Yellow River sediments remains poorly understood. Here, we conducted a comprehensive analysis of six distinct iron fractions: carbonate iron (Fe_carb), reducible (amorphous) iron oxides (Fe_ox1), reducible (crystalline) iron oxides (Fe_ox2), magnetite (Fe_mag), poorly reactive iron (Fe_PR), and non-reactive iron (Fe_U) in the Yellow River mainstream sediments to elucidate their distribution patterns and influencing factors. Our findings reveal that lithogenic inputs from the Loess Plateau facilitate magnetite formation through precipitation and redox processes, while the human intervention through Water–Sediment Regulation Scheme substantially modifies hydrodynamic conditions downstream of the Xiaolangdi dam, thereby altering iron fractions distribution patterns. Significant correlations of iron fractions between specific iron fractions and various heavy metals (Cu, Mn, V) as well as Total Organic Carbon (TOC), demonstrating the crucial role of iron in heavy metal and organic matter enrichment processes. These insights advance our understanding of iron fractionation dynamics in large river systems and provide a scientific foundation for developing sediment management strategies in the Yellow River basin.</p>