: Obesity is clinically known to be associated with an increased risk and aggravated pathology of Alzheimer's disease (AD). A high-fat diet (HFD), the major contributor to obesity, induces neuroinflammation and central insulin resistance, both of which are linked to synaptic dysfunction. Our previous studies demonstrated that avenanthramide-C (Avn-C), a natural oat-derived phenolic compound, exerts anti-inflammatory effects and alleviates synaptic dysfunction in conventional AD models. The present study aimed to elucidate the underlying mechanisms of Avn-C in obesity-accelerated AD. : Two-month-old male 5×FAD mice were fed an HFD to induce obesity and then treated with Avn-C. Cognitive performance, synaptic function, and structure were assessed via behavioral tests, electrophysiological recordings, and Golgi-Cox staining, respectively. Cytokine levels were quantified using ELISA and Western blotting. To explore the underlying mechanism, the NOD1 agonist C12-iE-DAP was administered to evaluate its effect on Avn-C-mediated neuroprotection. : Avn-C reduced Aβ deposition, enhanced the expression of synapse proteins, and restored synaptic plasticity, thereby improving both spatial and recognition memory in obese 5×FAD mice. Furthermore, Avn-C reduced neuroinflammation by inhibiting the NOD1/RIP2/NF-κB signaling pathway. Co-treatment with C12-iE-DAP abolished the beneficial effects of Avn-C on neuroinflammation, Aβ pathology, and cognitive function. : These results suggest that Avn-C mitigates obesity-exacerbated AD-like pathological features by suppressing NOD1/RIP2/NF-κB-mediated neuroinflammation and could be a new potential therapeutic strategy for obesity-associated AD.