<p>Co-occurring contaminants in riparian soils posed a growing threat to the sustainable development of the Yellow River Basin. However, understanding of the co-occurrence patterns and key drivers of heavy metals (HMs), antibiotics, and neonicotinoid insecticides (NNIs) at the watershed scale remains limited. Therefore, we selected surface soil along the Yellow River to analyze its content characteristics, spatial patterns, and interrelationships. Detection rates of NNIs, antibiotics, and HMs in soils exceeded 99%. The average content of total NNIs (∑₈NNIs) was 5.118 ng/g, with thiacloprid (1.667 ng/g) being the predominant component (32.5%). Total antibiotics averaged 0.412 ng/g, dominated by quinolones (47.8%) and macrolides (30.9%). The concentrations of As, Cr, and Zn among the HMs were 5.7–18.0 μg/g, 53.4–91.1 μg/g, and 35.6–94.3 μg/g, respectively, exceeding their background values at 36%, 21%, and 37% of the sampling sites, respectively. Soil organic matter content and pH negatively correlated with NNIs but positively with HMs, while fine soil particles positively correlated with both. Furthermore, ∑₈NNIs (7.680 ng/g) and the contents of thirteen antibiotics (∑₁₃ABX, 13.956 ng/g) in corn-cultivated soils were higher than in other cropped types, while ∑₈NNIs (0.780 ng/g) and ∑₁₃ABX (0.003 ng/g) in reed marshes were lower than in other cultivated soils. Health and ecological risks were generally low across the study area, but some specific sites posed potential integrated contamination risks. The study provided scientific data on the environmental fate and risks of NNIs, antibiotics, and HMs in riparian soils of large-scale watersheds, and underscored the need for more efficient usage practices and integrated watershed management strategies.</p>