The aim of the present study was to evaluate the protective effects of krill oil (KO) administration and ischemic preconditioning (IPC) protocol using biochemical, histopathological and immunohistochemical parameters in a rat model. Limb ischemia was achieved by clamping the femoral arteries. Fifty rats were divided into five groups (n=50). Effect of IPC strategy and drug-reinforcement protocol was evaluated together or separately in the experimental groups. Malondialdehiyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and catalase (CAT) activities were measured. Light microscopic images were supported by histological damage score findings and semiquantitative analysis findings of β-actin protein. Biochemical markers of oxidative stress were improved in KO and IPC groups compared with I/R group. The administration of IPC and KO resulted in a significant decrease in the damage score, 40% reduction of damage levels. Semiquantitative H-score analysis revealed that immunoreactivity increased in the treatment groups compared with I/R and IPC groups. It is concluded that ischemic-preconditioning protocol and pre-treatment with KO provides potent protection ischemia-reperfusion injury.