Background and Objective: Doxorubicin administration induces hepatotoxicity by production of reactive oxygen species (ROS) and cytokines that result in imbalanced redox potential leading to oxidative stress and reduced levels of antioxidant enzymes. The purpose of this study was to evaluate the protective effect of Jasonia Montana aqueous extract-selenium Nanoparticles (JMAE-SeNPs) against Dox-induced liver toxicity in rats. Materials and Methods: JMAE-SeNPs were prepared and characterized in terms of particle size and zeta potential. Furthermore, the IC₅₀ of JMAE-SeNPs against Hep-G2 liver carcinoma cell line and LD₅₀ was calculated. A total of 84 adult albino rats were used to assess the liver protective activity of JMAE-SeNPs against DOX-induced liver toxicity in rats. Results: JMAE-SeNPs had size of around 25 nm with negative zeta potential of -36.8±0.62. Also, its IC₅₀ against Hep-G2 liver carcinoma cell line and LD₅₀ was equal to 166.78 μg mL^–1 and 1120 mg kg^–1 body weight, respectively. The daily oral administration of JMAE-SeNPs at concentrations of 1/50 LD₅₀ (25 mg kg^–1 body weight) and 1/20 LD₅₀ (50 mg kg^–1 body weight) for 30 days to rats treated with DOX (2.0 mg kg^–1 body weight) resulted in a significant improvement in plasma ALT, AST, AST and LDH as well as liver MDA, caspase-8, TNF- κB and IL-1β. Oral administration of JMAE-SeNPs, on the other hand, increased the activity of SOD, GPx and GSH in DOX-treated rats. Furthermore, JMAE-SeNPs almost normalized these effects of DOX in liver tissue. Conclusion: The biochemical and histological findings of our study demonstrated that JMAE-SeNPs have liver protective activity against DOX-induced liver toxicity in rats.