Ischemia-Reperfusion Injury (IRI) is characterized by temporary cessation followed by restoration of blood supply and re-oxygenation of a certain organ. In the kidney, IRI contributes to Acute Kidney Injury (AKI) with rapid kidney damage and high morbidity and mortality rates. A surgical or drug-induced blockage of renal sympathetic nerve prevents, partially, the development of IR-induced AKI. Modulation of the Cholinergic Anti-Inflammatory Pathway (CAP) by Vagal Nerve Stimulation (VNS) has also a delayed but effective impact in renal IRI. However, the combined effect of renal sympathectomy and VNS had not been well investigated. Objectives: This work aimed at investigating the combined effect of VNS and Renal Denervation (RDN) in preventing deleterious effects of IRI in rats compared to the effects obtained by RDN alone and to elucidate the possible mechanisms. Methods: 32 adult male albino rats were equally allocated into four groups, sham group, IRI group, RDN group subjected to RDN before IRI and a group subjected to RDN and VNS before IRI. Results: Compared to the sham group, renal IRI led to the elevation of BUN, serum creatinine and MDA levels, it also elevated TNFα and reduced GPX activity and nitrate levels in the renal tissue. In addition, IRI lowered BCL2 in the immune-histochemical study and caused renal damage as observed by the histological light and electron microscopic examination. On the other hand, RDN demonstrated partial correction while, a combination of RDN and VNS demonstrated nearly optimum recovery of renal functions, oxidant/antioxidant balance, inflammatory markers as well as marked amelioration of immunohistochemical, structural and ultra-structural studies. Conclusion: VNS augmented and accelerated the renoprotective effects of RDN owing to its antioxidant, antiinflammatory as well as anti-apoptotic effects. Additionally, when VNS was combined to RDN, the protection against acute renal failure induced by IRI was rapid and effective.