Objective The aim of this study was to investigate the effect and protective mechanism of reduced glutathione on liver injury and fibrosis induced by carbon tetrachloride (CCl4) in rats. Methods Male Sprague-Dawley (SD) rats were treated with CCl4 and given normal saline and protoglutathione respectively. Biochemical indexes (ALT,AST, ALP) and inflammatory factors (IL-6, TNF-a, and IL-1β) were measured in the blood of rats. Histopathological analysis, expression of fibrosis marker proteins, pro-fibrosis signaling molecules, and Nrf2/ARE pathway related proteins were performed in liver tissues. Results Glutathione improved CCL4-induced liver injury and decreased the expression of inflammatory factors. Glutathione also ameliorates hepatic oxidative stress by reducing the expression of fibrotic marker proteins and pro-fibrotic signaling molecules, as well as reducing lipid peroxides and malondialdehyde levels and increasing glutathione content. In addition, glutathione can activate the Nrf2/ARE pathway, increase the expression of Nrf2 downstream antioxidant genes, and alleviate CCL4-induced oxidative stress in rat liver. Conclusion Glutathione in vivo protects the rat liver from CCL4-induced damage and fibrosis, which is associated with inhibiting HSC activation and alleviating oxidative stress