Kidney transplantation offers a longer life expectancy and better quality of life for patients with end-stage kidney disease compared to dialysis. Ischemia-reperfusion injury (IRI) is a critical factor in delayed or reduced graft function and increases the risk of rejection by enhancing organ immunogenicity. IRI occurs when blood supply to an organ is temporarily reduced and then restored, leading to various biological pathways such as transcriptional reprogramming, apoptosis, necrosis, immune responses, and endothelial dysfunction. Tubular cells primarily rely on fatty acid β-oxidation for energy production, but IRI disrupts this process, leading to ATP depletion and cellular damage. The complement system, which includes classical, alternative, and lectin pathways, plays a significant role in IRI by activating the membrane attack complex (MAC) and causing immediate kidney damage. The activation of innate and adaptive immune responses further exacerbates IRI by recruiting immune cells and cytokines, leading to tissue damage and inflammation. Targeting the complement system, particularly through blocking C5a receptors, has shown promise in reducing IRI and improving graft outcomes. Additionally, organ preservation techniques and ex vivo machine perfusion have shown potential in reducing kidney injury during transplantation. However, a comprehensive understanding of the complex pathophysiological mechanisms of IRI is necessary to develop effective therapeutic strategies.Kidney transplantation offers a longer life expectancy and better quality of life for patients with end-stage kidney disease compared to dialysis. Ischemia-reperfusion injury (IRI) is a critical factor in delayed or reduced graft function and increases the risk of rejection by enhancing organ immunogenicity. IRI occurs when blood supply to an organ is temporarily reduced and then restored, leading to various biological pathways such as transcriptional reprogramming, apoptosis, necrosis, immune responses, and endothelial dysfunction. Tubular cells primarily rely on fatty acid β-oxidation for energy production, but IRI disrupts this process, leading to ATP depletion and cellular damage. The complement system, which includes classical, alternative, and lectin pathways, plays a significant role in IRI by activating the membrane attack complex (MAC) and causing immediate kidney damage. The activation of innate and adaptive immune responses further exacerbates IRI by recruiting immune cells and cytokines, leading to tissue damage and inflammation. Targeting the complement system, particularly through blocking C5a receptors, has shown promise in reducing IRI and improving graft outcomes. Additionally, organ preservation techniques and ex vivo machine perfusion have shown potential in reducing kidney injury during transplantation. However, a comprehensive understanding of the complex pathophysiological mechanisms of IRI is necessary to develop effective therapeutic strategies.