AbstractSilicon dioxide nanoparticles (SiO₂NPs) are extensively used in cosmetics, food, and drug delivery. The main mechanism of SiO₂NPs toxicities depends on oxidative stress. Ginseng (Panax ginseng Meyer) is used in various medicinal applications because of its antioxidant efficiency. Therefore, the present study was carried out to investigate the possible combated role of ginseng against SiO₂NPs toxicity in rat liver. Thirty‐five male rats (160–180 g) were allocated into five groups of seven rats each, randomly. The first group was used as a control while groups 2, 3, 4, and 5 were treated orally with ginseng (Gin; 75 mg/kg, 1/10 LD₅₀), SiO₂NPs, (200 mg/kg, 1/10 LD₅₀), Gin + SiO₂NPs (protection group), and SiO₂NPs + Gin (therapeutic group) for 5 weeks, respectively. Treatment with SiO₂NPs increased lipid peroxidation, liver function enzymes, and decreased antioxidant enzymes (SOD, CAT, GPx, GST) activity and non‐enzymatic antioxidant (GSH) level. SiO₂NPs administration motivated liver apoptosis as revealed by the upregulation of the apoptotic genes, Bcl2‐associated x protein (Bax), and Beclin 1 and downregulation of the anti‐apoptotic gene, B‐cell lymphoma 2 (Bcl2) as well as increase in DNA damage. Also, SiO₂NPs administration caused inflammation as indicated by upregulation of the inflammation‐related genes (interleukin 1 beta [IL1β], tumor necrosis factor‐alpha [TNFα], nuclear factor kappa B [NFκB], cyclooxygenase 2 [Cox2], transforming growth factor‐beta 1 [TGFβ1]) as well as cell cycle arrest in the G0/G1 phase of liver cells. Moreover, histopathological examination proved the biochemical and molecular perturbations occurred due to SiO₂NPs toxicity. On the other hand, ginseng caused a significant modulation on the deleterious effects induced by SiO₂NPs in rat liver. In conclusion, ginseng has a potent preventive effect than the therapeutic one and might be used in the treatment of SiO₂NPs hepatotoxicity.