Mefenamic acid, a non-steroidal antiinflammatory drug (NSAID), directly and dose-dependently exhibits neuroprotective activity. In our study, we investigated the effects of mefenamic acid against D-serine on oxidative stress in the hippocampus, cortex and cerebellum of rats. Furthermore, the potential inflammatory and apoptotic effects of D-serine and potential protective effect of mefenamic acid were determined at mRNA and protein levels of TNF-alpha, IL-1 beta, Bcl-2 and Bax. We found that D-serine significantly increased oxidative stress, levels of inflammation-and apoptosis-related molecules in a region specific manner. Mefenamic acid treatment provided signifi cant protection against the elevation of lipid peroxidation, protein oxidation, levels of TNF-alpha, IL-1 beta and Bax. As a conclusion, we suggest that D-serine, as a potential neurodegenerative agent, may have a pivotal role in the regulation of oxidative stress, inflammation and apoptosis; and NSAIDs, such as mefenamic acid, may assist other therapeutics in treating disorders where D-serine-induced neurotoxic mechanisms are involved in.