Objective To investigate the effect of histone deacetylase inhibitor Tacedinaline (CI994) on acute kidney injury in mice. Methods Forty mice were randomly divided into four groups: sham group, CI 994 group, CCl4 group, and CCl4 + CI994 group. CCl4 was intraperitoneally injected into mice. Mice was administrated with CI994 intraperitoneally 6 hours and 24 hours post CCl4 insult. Mice in sham group received normal saline and CCl4 alone was administrated in CCl4 group. The levels of urea nitrogen (BUN), creatinine (Src), Cystatin C (Cys C), malondialdehyde (MDA), superoxide dismutase (SOD) and Cytochrome P450 2E1 (CYP2E1) were measured. H&E staining was performed to further confirm tissue injury. Western blot analysis of acetylated histone H3 and chromatin immunoprecipitation of HNF-1a on CYP2E1 promoter were performed. Results CCl4 injection induced acute kidney damage as determined by histological analysis and serological testing. Compared with sham group, treatment with CI994 significantly reversed the upregulation of serum BUN, Src and Cys C induced by CCl4 (P < 0.05). CCl4 induced increase of MDA and CYP2E1 and decrease of SOD were reversed by CI994 treatment (P < 0.05). H&E staining also revealed that CI994 treatment led to recovery of kidney injury induced by CCl4 injection. Furthermore, western blot suggested that acetylation of H3 upregulated with CI994 treatment. Immunoprecipitation indicated that binding of HNF-1α on CYP2E1 promoter was significantly increased following CI994 treatment (P < 0.05). Conclusion CI994 protects kidney through downregulation of CYP2E1.