This study was aimed at investigating the possible protective mechanism of royal jelly (RJ) against hepatotoxicity induced by cadmium chloride (CdCl2). The study included four groups: the control group received saline (0.9% sodium chloride), CdCl2 group received 6.5 mg/kg CdCl2 for seven days, RJ group received 85 mg/kg standardized RJ containing 6% 10-hydroxy-2-decenoic acid equivalent to 250 mg crude RJ, and finally, the fourth group received RJ 2 h before CdCl2 injection daily for 7 days. Oxidant/antioxidant markers of liver function estimation and histopathology were determined. The results revealed that RJ significantly ameliorated the hepatotoxic side effects of Cd. Furthermore, RJ inhibited oxidative stress, inflammation, and hepatic tissue injury; normalized enzymatic and nonenzymatic antioxidant molecules; and enhanced nuclear-related factor-2 (Nrf-2) expression. Our results provide new insights into the hepatoprotective property of RJ and revealed that RJ prevented hepatic injury, oxidative stress, and inflammation by upregulating Nrf2 and the anti-apoptotic protein Bcl-2. Hence, RJ can be used as a hepatoprotective agent against the toxic effects of CdCl2.