Ischemia–reperfusion injury (IRI) is a major cause of acute kidney injury and can lead to chronic kidney disease, with the complement system playing a key role, though the relative importance of early (C3) versus late (C5) components is unclear. In this study, IRI was induced in rats lacking C3 or C5, and kidney function, tissue damage, and proteomic changes were analyzed. Both C3 and C5 knockout rats showed strong protection, including improved kidney function, reduced tissue damage, and lower injury markers (KIM-1 and NGAL). C3 deficiency mainly enhanced metabolic and energy pathways while suppressing immune responses, whereas C5 deficiency primarily affected tissue remodeling with modest immune effects. Overall, blocking C3 had broader effects on kidney injury and repair than blocking C5, although both reduced damage, suggesting that targeting different parts of the complement system may offer therapeutic benefits.