<p>Per- and polyfluoroalkyl substances (PFAS) are persistent and potentially toxic compounds increasingly detected in aquatic environments, yet their occurrence, sources, and health risks in major watersheds remain under-characterized. This study provides a comprehensive assessment of PFAS contamination in the Nakdong River Basin, South Korea, through integrated analysis of spatial distribution, source apportionment, mass fluxes, and age-stratified human health risks. Surface water samples were collected from 23 sites across the mainstem and major tributaries during high-flow conditions. A total of 11 PFAS compounds were detected, with ΣPFAS concentrations (sum of PFAS) ranging from 9.28 to 171.40 ng/L. Concentrations of perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) exceeded the United State environmental protection agency (USEPA) maximum contaminant levels at several sites. Land-use analysis revealed that industrial and wastewater treatment plant (WWTP) affected tributaries showed the highest PFAS levels and detection frequencies. Positive matrix factorization (PMF) modeling identified four source profiles linked to domestic wastewater, industrial discharge, electronics manufacturing, and secondary re-entry. Mass flux calculations indicated that tributaries such as GA-3 and IG-3 contribute disproportionately to basin wide PFAS transport. Human health risk assessment using mixture hazard quotients (HQ_mix) showed that children (0–5 years) exceeded the precautionary risk threshold of 0.1 at six sites, despite all values remaining below 1.0. These findings highlight the need for integrated monitoring and land-use-informed management strategies to mitigate PFAS exposure, especially in vulnerable populations. The study provides critical insights for targeted regulation and sustainable watershed protection in PFAS impacted regions.</p>