Nilotinib as a tyrosine kinase inhibitor has been recently used to improve the liver fibrosis process, but the exact mechanisms still require further clarification. In this study, we investigated the anti-fibrotic effects of Nilotinib via RAGE/HMGB1axis and antioxidant mechanisms. This experimental study was performed in the Hamadan University of Medical Sciences, Iran, from May 2015 to December 2016. Liver fibrosis was induced in Wistar male rats by CCL₄. Rats were gavaged daily with Nilotinib (10 mg/kg). RAGE, HMGB1, TNF-α and TGF-β mRNA expression were evaluated by quantitative RT-PCR. TNF-α protein levels were measured using the immunoassay method. Thiol groups, carbonyl groups, nitric oxide levels and glutathione peroxidase activity were measured by spectrophotometric methods.The results showed that Nilotinib decreased TNF-α, TGF-β, RAGE and HMGB1 mRNA expression (p<0.001) in the liver tissues of the fibrosis group. Nilotinib also decreased carbonyl groups and nitric oxide levels and increased thiol groups and glutathione peroxidase activity in the fibrosis groups. The histopathological changes were found to be attenuated by Nilotinib. In conclusion, Nilotinib can improve liver fibrosis and open new mechanisms of the anti-fibrotic properties of Nilotinib.