The main objective of the present work was to study, for the first time, the effect of naturally-derived compounds Chitosan (CS), Silibinin (SB) and their combination in different doses on the expression level of both p21 and p53 genes in Ehrlich ascites carcinoma (EAC) bearing mice considered as a model for the cancer. The aim was to evaluate the antitumor activity, lipid peroxidation, nitrosative stress, antioxidant status of CS, SB and combination treatment of both against EAC in female Swiss albino mice and to provide a first comparative assessment in this regard. Results: Treatment either with CS or SB alone has significantly inhibited tumor growth in a dose-dependent manner as compared to the control. Furthermore, the highest antitumor activity was resulted by SB treatment (75 mg/kg body wt) where 87.5% of treated animals showed a complete response meaning complete disappearance of tumors. The second highest antitumor activity was obtained by using combination treatment of both CS 25 mg/kg and SB 50 mg/kg where 66.67% of animals showed complete disappearance of tumors. Significant increase in superoxide dismutase (SOD) activity was observed after treatment using CS, SB and their combination. SB treatment exhibited a significant decrease in malondialdehyde (MDA) level, while no significant decrease was observed using CS alone or in combination with SB. SB (50 mg/kg) showed a significant decrease in cellular nitric oxide (NO) level; however, no significant change was observed when using CS alone or in combination with SB. Significant increase in p21 gene expression was observed using SB (50 mg/kg), CS (25 mg/kg) and combination of both. Using these doses showed synergistic additive effect. Conclusion: SB alone or in combination with CS was shown to be superior than CS alone, as an antitumor agent under the same experimental conditions by modulating as well as decreasing lipid peroxidation and augmenting the antioxidant defense system in EAC-bearing mice. Furthermore, antitumor effect of SB correlated with upregulated p21 gene expression and cell cycle arrest, while it had no significant effect on p53 gene expression. Finally, we suggest the therapeutic potential of using a novel combination of naturally derived compounds (CS and SB) as a target therapy for treatment of cancer; however, this combinatorial treatment deserves more investigation in the future.