Coenzyme Q (CoQ) 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 CoQ against hepatic ischemia reperfusion (IR) injury. Our results revealed that CoQ significantly improved hepatic dysfunctions and oxidative stress caused by IR injury. Interestingly, as compared to IR subjected rat, CoQ inhibited apoptosis by marked down-regulation of both Bax and PUMA genes while the level of Bcl-2 gene was significantly increased. Moreover, CoQ up-regulated PI3K, Akt and mTOR protein expressions while it inhibited the expression of both GSK-3β and β-catenin. Additionally, CoQ restored oxidant/antioxidant balance via marked activated Nrf-2 protein as well as up-regulation of both Sirt-1 and FOXO-3 genes. Moreover, CoQ 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 CoQ remarkably ameliorated the histopathological damage induced by IR injury. Taken together, our results suggested and proved that CoQ provided a hepato-protection against hepatic IR injury via inhibition of apoptosis, oxidative stress, inflammation and their closed related pathways.