Abstract Background: Fatty acid-binding proteins (FABPs) influence cellular energy metabolism through the regulation of fatty acid kinetics and play a crucial role in neuronal apoptosis following cerebral infarction. Resveratrol (RSV) has been shown to mediate neuroprotective effects in ischemic stroke; however, its regulatory impact on FABPs and associated pathways remains to be elucidated. Methods & Results: WGCNA analysis reveals that FABP5 was significantly enriched in fatty acid metabolism-related pathways in middle cerebral artery occlusion (MCAO) rats. Modulating FABP5 expression may influence post-infarction neuronal recovery. Molecular docking experiments demonstrated that resveratrol (RSV) exhibits strong binding affinity with FABP5. After administering different doses of RSV to MCAO rats, the cerebral infarct area significantly decreased, and neurological function improved with increasing doses. Concurrently, the expression of FABP5 and NSE in brain tissue was downregulated, while BDNF expression was upregulated, and neuronal morphology improved. Further experiments using FABP5 overexpression and inhibition models revealed that FABP5 overexpression exacerbated neuronal apoptosis and suppressed AMPK protein expression, whereas FABP5 inhibition reduced neuronal apoptosis and enhanced AMPK protein expression. Conclusion:RSV down-regulates FABP5 expression in cerebral infarction tissues and potentially mediates the AMPK-related pathway to ameliorate neuronal apoptosis.