With the development of technology, drugs are being developed for different purposes. Thus, the rate of drug injury considerably increased worldwide. Liver is the largest detoxification organ in the human body, but it is also the organ most vulnerable to drug damage. Ginsenoside Rg1 has been reported to have an extensive protective effect on liver injury. However, no evident results showed whether ginsenoside Rh1 could improve the injury caused by drugs. Therefore, this paper aimed to explore the protective effect in a mouse model with liver injury. Mice administered with acetaminophen (APAP) were used as the negative group, while those administered with Rg1 (10, 20, and 30 mg/kg) and Rh1 (10, 20, and 30 mg/kg) were used as the prevention groups. Results indicated that the treatments increased the levels of GSH and SOD remarkably and decreased that of MDA. In addition, the expression levels of GOT and GPT was remarkably reduced compared with the negative group. Inflammatory agents TNF-α, IL-6, and IL-1β were also decreased by the treatments. Meanwhile, Rg1 and Rh1 not only prevented the expression of Bax but also promoted Bcl-2 levels in mice. All results suggested that ginsenoside Rg1 and ginsenoside Rh1 exerted a preventive effect on APAP-induced liver injury in mice. PRACTICAL APPLICATIONS: With the increasing number of patients suffering from drug-induced liver injury, it is urgent to find alternative natural plant drugs to treat liver injury. This paper focuses on the protective effects of Ginsenoside Rg1 and ginsenoside Rh1 on acetaminophen (APAP) induced liver injury. From the previous studies, we found that there is no sufficient evidence to show that ginsenoside Rh1 has protective effect on liver injury. In this paper, the detection of oxidative stress indicators, liver histopathological analysis and immunoprotein analysis show that both ginsenoside Rg1 and ginsenoside Rh1 have preventive effect on liver injury caused by APAP, which provides a reference for the follow-up experimental research.