Possible cardioprotective effect of Kolaviron (KV) administration and the molecular mechanism (s) involved in ischaemic/reperfusion injury of isolated rat hearts were assessed. Twenty rats were used for this study. They were grouped into ten rats of group of two. Rats in group I received 2ml/kg of corn oil (vehicle) while animals in groups II received 200 mg/kg body weight of Kolaviron (KV) for four weeks respectively. Isolated rat hearts were stabilized for 5 minutes on Langendorff, perfused on working heart model for 10 minutes and subjected to global ischaemia for 15 minutes followed by 25 minutes reperfusion. Antioxidant enzymes, markers of oxidative stress and western blot analyses were carried out on snap-frozen heart tissues. There was significant (p<0.05) increase in superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx), oxygen radical absorbance capacity (ORAC) and concomitant significant (p<0.05) decrease in malondialdehyde (MDA) and intracellular reactive oxygen species (ROS) in isolated rat hearts of animals that received KV compared to the control. Western blot analysis revealed significant up-regulation of Akt/PKB, p- Akt/PKB, HSP27, p-HSP27 and down-regulation of p38 MAPK, Caspase 3, cleaved Caspase 3and cleaved PARP. Taken together, KV offered cardioprotection by enhancing the expression of pro-survival signaling pathway and abrogation of apoptotic pathway in isolated rat hearts subjected to ischaemic/reperfusion injury