Reactive oxygen species play a role during brain injury due to closed head trauma. Enzymatic or nonenzymatic antioxidants may protect brain tissue against oxidative damage. The present study was performed to assess the changes of endogenous indices of oxidative stress in serum from rats subjected to head trauma and whether treatment with propofol and/or erythropoietin (EPO) modifies the levels of endogenous indices of oxidative stress. For these purposes, female Wistar Albino rats were divided into five groups: non-traumatic sham group, trauma performed control, trauma with propofol (i.p.), trauma with EPO (i.p.) and trauma with propofol and EPO performed study groups. At the end of the experimental procedure, blood was taken by cardiac puncture to determine superoxide dismutase (SOD) and xanthine oxidase (XO) activities as well as malondialdehyde (MDA) and nitric oxide (NO) levels in serum. Serum MDA level of control traumatic brain injury (TBI) group was significantly higher than sham operation group ( p < 0.012). Serum MDA levels in propofol, EPO and propofol + EPO groups were found to be decreased in comparison with control group ( p < 0.039, p < 0.030 and p < 0.018, respectively). Serum NO level was found to be increased in TBI group, but difference was not statistically significant when compared to sham-operated group ( p = 0.092). Propofol, EPO and propofol + EPO administration efficiently reduced serum NO levels to reach sham-operated group ( p < 0.002, p < 0.001 and p < 0.015, respectively). These results suggested that acute administration of both propofol and EPO altered the indices of oxidative stress similarly against brain injury due to trauma.