Perfluorooctanoic acid (PFOA) is linked to metabolic disease, yet its impact on hepatic metabolism remains unclear. We exposed Western diet-fed mice to environmentally relevant PFOA and found that it did not cause classical hepatic steatosis. Instead, PFOA produced a cachexia-like phenotype, with peripheral fat loss, hepatomegaly, liver injury, and systemic inflammation, together with a paradoxical lipid response in which circulating lipids and hepatic lipid droplets fell while hepatic cholesterol rose. By combining metabolomics, 4D-DIA proteomics, network toxicology, and deep-learning, we identified EGFR as a shared target of PFOA and naringenin (NAR). PFOA bound EGFR, hyperactivating EGFR-STAT3 signaling to accelerate fatty acid oxidation and SREBP2-driven cholesterol biosynthesis, while inflammation suppressed HSD11B2 and raised corticosterone. NAR engaged the same target, restrained this signaling, and reversed metabolic dysregulation and inflammation while restoring HSD11B2. Ultimately, PFOA hepatotoxicity is not driven by steatosis and identify EGFR as a candidate target in pollutant-associated metabolic disease.