Objectives This study evaluated the protective efficacy of combination treatment with ginsenoside-Mc1 and silibinin against hepatic ischemia-reperfusion (IR) injury in diabetic-aged rats, and further explored AMPK's role in this protection. Methods A high-fat diet/streptozotocin was used to induce type-2 diabetes in aged rats (20-24 months). Diabetic-aged rats were pretreated with ginsenoside-Mc1 (10 mg/kg, IP) and silibinin (50 mg/kg, IP), alone or in combination, for 4 weeks before induction of hepatic IR injury. Results Induction of IR injury in diabetic-aged rats significantly elevated plasma levels of hepatic alanine and aspartate aminotransferases and negatively affected liver histology. Levels of 8-isoprostane, ROS production, Bax, and cleaved-caspase-3 expression were higher and manganese-superoxide dismutase (MnSOD), glutathione, and Bcl2 and p-AMPK were lower in IR-receiving group. In comparison to individual treatments, the combination of ginsenoside-Mc1 and silibinin powerfully restored IR-induced changes in liver enzymes and histopathological indices, oxidative markers, AMPK, and apoptotic protein expressions. Inhibition of AMPK using compound-C in H2O2-stimulated HepG2 cells significantly abolished the protective effects of combination treatment. Conclusions Combination of ginsenoside-Mc1 and silibinin was superior to their alone usage in protecting hepatocytes of diabetic-aged rats from oxidative/apoptotic damages following IR injury, through an AMPK-mediated mechanism.