Arsenic is a common environmental toxicant. Long-term arsenic exposure can induce various types of liver injury, but the underlying mechanism remains unclear, so effective prevention and treatment measures are unknown. This study aims to explore the mechanism of arsenic-induced rat liver injury based on the histone H3K18 acetylation-dependent antioxidant pathway and to identify the role of a medicinal and edible resource,Rosa roxburghii Trattjuice, in combating it. Hepatic steatosis and inflammatory cell infiltration were observed in rats exposed to different doses of NaAsO2using histopathological measurement. Increased 8-OHdG and MDA in liver tissue corroborated hepatic oxidative damage. We further found that a reduction in H3K18ac in the liver showed a dose–response relationship, with an increase in the NaAsO2treatment dose, and it was remarkably associated with increased 8-OHdG and MDA. The results of ChIP-qPCR identified that the decreased enrichment of H3K18ac in promoters of theHspa1aandHspb8genes culminated in the inhibition of the genes’ expression, which was found to be involved in the aggravation of hepatic oxidative damage induced by arsenic. Notably,Rosa roxburghii Trattjuice was found to reduce 8-OHdG and MDA in the liver, thereby alleviating the histopathological lesions induced by arsenic, which was modulated by recovering the H3K18ac-dependent transcriptional activation of theHspa1aandHspb8genes. Taken together, we provide a novel epigenetics insight into clarifying the mechanism of arsenic-induced liver injury and its rescue byRosa roxburghii Trattjuice.