Background Obstructive sleep apnea (OSA) in humans chronically promotes the neuronal damage in the hippocampus. Toll-like receptor 2 (TLR2) is pivotal for the development of numerous hippocampal diseases. Chronic intermittent hypoxia (CIH) is a prominent feature of OSA. Here in our study, the effects of TLR2 antagonism on the neural damage elicited by CIH were examined. Methods Ortho-vanillin (O-vanillin) is an inhibitor of TLR2. Adult male mice were subjected to 8 h of intermittent hypoxia per day with or without O-vanillin for 28 days. Neuronal damage, the number of microglia, the interaction of TLR2 with its adapter protein myeloid differentiation factor 88 (MYD88), the expressions of inflammatory cytokines, and the oxidative stress were observed. Results O-vanillin inhibited the increased interaction of TLR2 and MyD88, the activation of NF kappa B, the aggregation of microglia, the overexpression of proinflammatory agents, the elevation of oxidative stress, and hippocampal neuron cell apoptosis induced by CIH. Conclusions Our experiments indicate that TLR2 antagonism may alleviate the hippocampal neuronal damage caused by CIH via inhibiting neuroinflammation and oxidative stress.