Background: Abdominal aortic aneurysms and peripheral artery disease pose significant health risks, ranking third after heart attacks and cerebral strokes. Surgical interventions often involve temporary aortic clamping, leading to ischemia–reperfusion injury and tissue damage. Colchicine and mesenchymal stem cells have shown promise, individually, in mitigating ischemia–reperfusion injury, but their combined effects remain understudied. Methods: This study utilized 42 male Wistar rats, divided into six groups: Control, Sham, Ischemia–Reperfusion, Colchicine, Mesenchymal stem cell, and Mix (colchicine and mesenchymal stem cell). The ischemia–reperfusion model involved clamping the abdominal aorta for 60 min, followed by 120 min of reperfusion. Colchicine and mesenchymal stem cell treatments were administered as pre- and post-ischemia interventions, respectively. Mesenchymal stem cells were cultured, characterized by flow cytometry, and verified for specific surface antigens. Blood and tissue samples were analyzed for oxidative stress markers, nitric oxide metabolites, and apoptosis using TUNEL. Results: There were significant differences between the groups in terms of the serum total antioxidant capacity (p < 0.001) and inflammation markers (ischemia-modified albumin, p = 0.020). The combined therapy group (Mix) exhibited the lowest inflammation levels. Arginine levels also showed significant variation (p = 0.028), confirming the ischemia–reperfusion injury model. In muscle tissues, the total antioxidant capacity (p = 0.022), symmetric dimethylarginine, and citrulline levels (p < 0.05) indicated nitric oxide metabolism. Apoptosis was notably high in the ischemia–reperfusion injury group as anticipated. It appeared to be reduced by colchicine, mesenchymal stem cells, and their combination, with the most significant decrease observed in the Mix group (p < 0.001). Conclusions: This study highlights the potential of using combined colchicine and mesenchymal stem cell therapy to reduce muscle damage caused by ischemia–reperfusion injury. Further research is needed to understand the underlying mechanisms and confirm the clinical significance of this approach in treating extremity ischemia–reperfusion injuries.