This study investigated the large-scale distributions of persistent toxic substances (PTSs) and heavy metals in sediments of the Yellow Sea, collected from six transects between latitudes 32 and 37 degrees north (n = 35). Elevated concentrations of polychlorinated biphenyls (PCBs) were detected near the mainland, with a predominance of low-chlorinated congeners (di to tetra, ∼60%), indicative of atmospheric deposition. Analysis of traditional and emerging polycyclic aromatic hydrocarbons (t-PAHs and e-PAHs) revealed notable enrichment in the Central Yellow Sea Mud Zone (CYSM), attributing fossil fuel combustion as the significant source. Styrene oligomers and alkylphenols exhibited notable accumulation near the Han River Estuary in South Korea and the Yangtze River Estuary in China, respectively. The accumulation of heavy metals was predominantly observed in the CYSM, with element-specific distribution patterns. Cluster analysis revealed distinct distribution patterns for PTSs and metals, highlighting their source-dependent and grain size-dependent behaviors. In addition, the distribution and accumulation of PTSs tended to depend on their partitioning coefficients, such as the octanol-air partition coefficient (log KOA) and octanol-water partition coefficient (log KOW). This study offers valuable insights into the sources, transport, and fate of hazardous substances in the Yellow Sea, emphasizing the necessity for targeted environmental management strategies.