Acetaminophen (APAP) is one of the few recommended analgesic and antipyretic drugs in some critical cases such as viral disease COVIDâ19. However, the unrestricted use of APAP develops liver disorders. Hepatotoxicity and liver injury can also be induced by ionizing radiation (IR) during radiotherapy. The data of the current study represents that treatment of rats with either APAPâoverdose, or gammaâirradiation (R) induces hepatotoxicity, results in significant increases of the hepaticâenzymes activities (ALT, AST, ALP, GGT, LDH, and MDH), as well as enhancement of triglycerides, total cholesterol levels, combined with declines in albumin and total protein contents. An enhancement of the lipid peroxides (malondialdehyde; MDA), and nitric oxide levels along with a decline of reduced glutathione contents and suppression of superoxide dismutase, catalase, and glutathione peroxidase activities are also observed within the liver tissues of intoxicated animals. TNFâα, ILâ1ÎČ, ILâ6, iNOS, Cytochrome P450 2E1 (CYP2E1), miRâ802 gene expression, NFâÎșB, and calcium levels are upâregulated, while Nuclear factor erythroidârelated factorâ2 (Nrf2), Hemoxygenaseâ1 (HOâ1) protein and gene expressions, as well as, glutamateâcysteine ligase catalytic subunit (GCLC), NAD(P)HâQuinone oxidoreductase (NQO1), and miRâ122 gene expressions are downâregulated in the livers of intoxicated animals. All these parameters show significant improvement in R/APAP intoxicated animals. Curcumin pretreatment develops an amelioration of these effects in APAPâoverdose, Râexposure, or R/APAP treatments. In conclusion, oral administration of curcumin shows hepatoprotective effects against APAPâoverdose induced hepatic damage in normal and gammaâirradiated rats through prospective regulation of the therapeutic targets CYP2E1, Nrf2, and NFâÎșB, via organizing the miRâ122 and miRâ802 gene expression.