Coenzyme Q₁₀ (CoQ₁₀) is a component of the mitochondrial electron transport chain and regarded as a strong anti-oxidant agent. In this study, we focused on the mechanistic insights involved in the hepato-protective effects of CoQ₁₀ against hepatic ischemia reperfusion (IR) injury. Our results revealed that CoQ₁₀ significantly improved hepatic dysfunctions and oxidative stress caused by IR injury. Interestingly, as compared to IR subjected rat, CoQ₁₀ inhibited apoptosis by marked down-regulation of both Bax and PUMA genes while the level of Bcl-2 gene was significantly increased. Moreover, CoQ₁₀ up-regulated PI3K, Akt and mTOR protein expressions while it inhibited the expression of both GSK-3β and β-catenin. Additionally, CoQ₁₀ restored oxidant/antioxidant balance via marked activated Nrf-2 protein as well as up-regulation of both Sirt-1 and FOXO-3 genes. Moreover, CoQ₁₀ strongly inhibited inflammatory response through down-regulation of NF-κB-p65 and decrease both JAK1 and STAT-3 protein expressions with a subsequent modulating circulating inflammatory cytokines. Furthermore, histopathological analysis showed that CoQ₁₀ remarkably ameliorated the histopathological damage induced by IR injury. Taken together, our results suggested and proved that CoQ₁₀ provided a hepato-protection against hepatic IR injury via inhibition of apoptosis, oxidative stress, inflammation and their closed related pathways.