Exhausting physical activity can cause harmful effects on the human, due to release of free radicals. This research is focused on effect of combined N-acetyl cysteine (NAC) and vitamin C (VC) supplementation on biomarkers of blood total antioxidant capacity (TAC), malondialdehyde (MDA) and C- reactive protein (CRP) during the exhaustive exercise in Wistar rats. This study was carried out on 32 female Wistar rats, which divided into 4 groups. In First group was given the effervescent tablets (NAC 600 mg, dissolved in water) four hours before the experiment by gavages. Second group received VC tablets (500 mg) and for third, a combination of VC and NAC (VICNAC), and fourth, was taken as the control group. Three stages of Blood samples were taken 1hour before starting, immediately after the exhaustive exercise, and after one hour at rest, respectively. After separating the serum samples; they were immediately stored at -80◦ C until analysis. The MDA, CRP and TAC concentrations were respectively measured using spectrophotometric and ELISA methods. A Significant reduction was observed in the concentration of MDA immediately after the exhaustive exercise in NAC group, in compared with the control (P ≤0.05); as well as CRP level in VICNAC group (P ≤0.05). There was no change in the TAC blood concentration during the study except in the NAC group one hour after exercise, which was significantly decreased in compared with the control groups (P≤0.05). In Conclusion, The results demonstrated that oral administration of NAC at least four hours before an exhaustive exercise can significantly decrease the harmful effects of oxidative stress in rats