Objectives: Evaluation of the prophylactic effect of resveratrol (RSV) on thioacetamide (TAA)-induced hepatotoxicity. Experimental Protocol: 50 albino rats have divided into a control group that received no medications, TAA group that received TAA intraperitoneal injection (200 mg/kg trice weekly for 4 weeks) and three groups that received 10, 20, and 40 mg/kg RSV for 6-wk and on the 3rd week TAA was injected as for TAA animals. Blood samples were collected for spectrophotometric estimation of serum activity levels of aspartate (AST) and alanine transaminase (ALT), total bilirubin (TB) and albumin, ELISA estimation of serum levels of tumor necrosis factor-α (TNF-α), Interleukin-6 (IL-6), IL-10, Malondialdehyde (MDA) and activity level of superoxide dismutase (SOD), and for estimation of gene expression levels of miR-21 and miR-155 using the quantitative reverse transcriptase polymerase chain (qRT-PCR). Results: Exposure to TAA disturbed liver functions, increased levels of inflammatory cytokines, initiates tissue lipid peroxidation and induced upregulation of expression levels of miR-21 and miR-155. RSV prophylaxis improved the TAA-induced effects and prevented the overwhelming TAA-upregulation of microRNAs in a dose-dependent manner, but this effect is more manifest in miR-155. Regression analysis suggested that an RSV dose of 28.2 mg/kg (95% CI: 23.72-32.68) as a prophylactic dose can reduce the hazard of TAA hepatotoxicity to 30%. Conclusion: TAA-hepatotoxicity might be mediated through the upregulation of gene expression levels of miR-155 and miR- 21 initiating a cascade that ended in liver fibrosis. Resveratrol prophylaxis may protect or at least ameliorate the TAA-hepatotoxicity mostly through improving the deregulated expression levels of microRNAs.