<p>Background: Observational studies have shown that exposure to per- and polyfluoroalkyl substances can lead to neurotoxicity. We focus on whether perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) affect brain morphology and the potential molecular mechanisms of toxicity. Methods: Causal relationship between exposure to both PFOA and PFOS and brain morphology was explored based on Mendelian randomization (MR), and the toxic molecular mechanism was investigated using network toxicology. Results: MR analysis indicated PFOA exposure reduced brain volume in left parahippocampal (<i>p</i> = 0.018) and right rostral anterior cingulate (<i>p</i> = 0.007), while PFOS exposure decreased volume in left middle temporal (<i>p</i> = 0.036), paracentral (<i>p</i> = 0.022), postcentral (<i>p</i> = 0.014), posterior cingulate (<i>p</i> = 0.002), rostral middle frontal (<i>p</i> = 0.040), superior frontal (<i>p</i> = 0.027), superior parietal (<i>p</i> = 0.033), and in the right hemisphere: inferior parietal (<i>p</i> = 0.017), superior frontal (<i>p</i> = 0.030), superior parietal (<i>p</i> = 0.025), and caudal middle frontal (<i>p</i> = 0.041). GO/KEGG analyses revealed 161 targets linked to the neurotoxicity of PFOA and PFOS, primarily associated with fatty acid metabolism, GABA signaling, neurotransmitter receptor activity, ferroptosis, and PPAR pathways. Molecular docking verified key targets (PPARG, FASN, SCD, CD36, GOT2) underlying the toxicity mechanism. Conclusions: Exposure to PFOA and PFOS leads to reduced brain volume - neurotoxicity at the macroscopic level. At the molecular level, we identified PPARG, FASN, SCD, CD36, and GOT2 as key targets implicated in the pathology of brain damage induced by PFOA and PFOS.</p> Graphical Abstract <p></p>