Perfluorooctanoic acid (PFOA) is a persistent organic pollutant associated with many adverse health risks. Evidence suggests that obese individuals may be more susceptible to environmental substances. In the present work, we explored the effects of PFOA exposure on the cognitive function and intestinal health of obese mice. Obese mice induced by a high-fat diet were exposed to PFOA (0.5 mg/kg (bw)/day) via drinking water for 100 days. After exposure to PFOA, decreased body weight, enlarged liver, abnormal behavior, impaired synapse structure, neuroinflammation, activated glial cell, decreased nerve growth factor, altered gut microbiota, and disturbed serum metabolites were observed, while the gut inflammation and intestinal barrier were not significantly influenced. These results suggest that exposure to PFOA is associated with cognitive impairment in obese mice. [Display omitted] [ABSTRACT FROM AUTHOR]