Currently, hepatic injury due to environmental pollutants extremely threatens human health and elicits great concern. Hence, there is a high global interest to find natural novel formulation products with potent hepatoprotective activity to combat liver disease. Hence, we evaluated the protective or therapeutic effect of hesperidin (HSP) and taurine (TAU), individually and in combination, on carbon tetrachloride (CCl)-induced acute hepatic injury in rats. The pre- or posttreatment by HSP and/or TAU significantly depressed CCl-induced elevation of alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, gamma-glutamyl transferase, total bilirubin, direct bilirubin, indirect bilirubin, malondialdehyde, globulins (α1, α2, β, and γ), albumin/globulin ratio, triglycerides, total cholesterol, high-density lipoprotein cholesterol, very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, nitric oxide, and myeloperoxidase levels. Also, the pre- or posttreatment by HSP and/or TAU significantly minimized CCl-induced reduction of superoxide dismutase, catalase, reduced glutathione, and albumin concentrations. Furthermore, the protective or therapeutic administration of HSP and/or TAU markedly restored the CCl-induced altered hepatic architecture, depleted glycogen, and DNA contents. Notably, alleviating CCl-induced hepatotoxicity was more prominent in the protective groups than the therapeutic groups. More importantly, most of biochemical and histopathological parameters of HSP+TAU did not significantly differ from those of separate TAU or HSP neither before nor after CCl exposure. Conclusively, HSP or TAU could be candidate protective agents against CCl hepatotoxic impacts but the combination of both bioactive offers only a limited synergistic effect. Graphical abstract.