Background: The delivery of selenium in a nano-form (Se-NPs) is a promising modality of treatment for various oxidative stress-induced diseases. Objective: This study aims to investigate the conceivable effects of selenium nanoparticles either alone (Se-NPs) or encapsulated with chitosan (Se-CS-NPs) on toxicity induced by CCl4 in rats. Methods: Eighty albino rats were divided equally into eight groups. The first group was the placebo. The second group was a positive control, while the third and the fourth groups got orally (Se-NPs 5 mg/Kg) and (Se-CS-NPs 225 mg/Kg) respectively. The fifth and sixth groups were protective groups in which Se-NPs or Se-CS-NPs were given simultaneously. The seventh and eighth groups were therapeutic as they received either Se-NPs or Se-CS-NPs after stopping the CCl4 injection for 4 weeks more. Results: Our results showed that the protective and therapeutic groups showed an increase in caspase-3 gene expression with a decline in the expression of Bcl-2, Nrf2, and AFP genes. Histopathological and immunohistochemical investigations showed the role of selenium nanoparticles either alone or coated with chitosan in decreasing fibrotic marker collagen I positive reaction Conclusion: Selenium nanoparticles showed an excellent effect in counteracting the toxic effect of carbon tetrachloride on liver functions, inflammation reactions, and apoptosis process. Moreover, using selenium nanoparticles has a strong role in preserving the liver architecture with its normal constituents. No additional benefit was observed when the selenium nanoparticles were encapsulated with chitosan.