Abstract: To the best of present knowledge, the possible protective effects of Caffeic Acid Phenethyl Ester (CAPE), on possible Isoniazid (INH) and Rifampicin (RIF) induced neurotoxic effects in brain tissue have not been investigated yet. As such, the purpose of this experimental study was to investigate the effects of CAPE, on INH and RIF induced neurotoxicity in rat brain tissue. We measured Total Antioxidant Capacity (TAC), Superoxide Dismutase (SOD) activities, Malondialdehyde (MDA) and nitric oxide (NO) levels in the brain tissue of rats. Male Sprague-Dawley rats were divided into eight experimental groups, with ten animals in each group. These groups are consist of control group, INH-treated group, RIF-treated group, INH+RIF treated group, INH+CAPE treated group, RIF+CAPE treated group, INH+RIF+CAPE treated group and CAPE treated group. MDA and SOD levels in brain tissue were significantly higher and TAC levels were lower in the INH, RIF and INH+RIF treated groups (p<0.05) and TAC levels were lower in the INH, RIF and INH+RIF groups than in the control group (p<0.05). CAPE plus INH and/or RIF treatment caused a significant decrease in MDA levels in brain tissue (p<0.05). In addition, CAPE plus INH and/or RIF treatment caused a significant increase in TAC levels (p<0.05). In conclusion, we have shown that administration of INH and RIF is accompanied by increased lipid peroxidation and oxidants in rat brain tissue. CAPE may protect against INH and RIF-induced neurotoxicity. Therefore, CAPE supplementation may be used as a potential neuroprotective drug for antituberculosis therapy with INH and/or RIF.