Background: Injury of the kidney due to ischemia-reperfusion (IR) provokes damage in remote organs. The anti-inflammatory and antioxidant activities of colchicine have previously been proven. Objective: This study planned to assess the renal and cardiac dysfunctions during different reperfusion intervals after renal ischemia and explore the protective effect of colchicine focusing on the role of the Nrf-2/HO-1 axis. Materials and Methods: Thirty-two rats divided into four groups (8 rat/group) were used to investigate the effect of ischemia and different periods of reperfusion. Then, another thirty-two rats were divided into four groups (8 rat/group); sham, 45 minutes I/24 hours R, 45 minutes I/24 hours R / colchicine, colchicine, and examine the antioxidant and inflammatory status. Results: Renal IR worsens the kidney and cardiac functions, exaggerates lipid peroxide formation, and histopathological alterations markedly after (45 minutes I/24 hours R). Colchicine pretreatment recovers the kidney and cardiac functions markers and lessening lipid peroxidation. Moreover, renal IR significantly decreased the nuclear factor erythroid 2- related factor 2 (Nrf-2) and heme oxygenase-1 (HO-1) expressions which alter the oxidant status and induce inflammation by increase the inflammatory mediator tumor necrosis factor-alpha (TNF-α). Colchicine pretreatment before renal IR significantly altered this insult by increase the levels of Nrf-2 and HO-1 which subsequent increment in TNF-α level. Conclusion: the vulnerability of the heart to injury after renal IR varies with the reperfusion period. In addition, colchicine conferred renal and cardioprotective effect against renal IR through its anti-inflammatory and antioxidant activities by modulation of Nrf-2/HO-1 hub.