Background: Shikonin (SKN) is a widely used Chinese Traditional Medicine with anti-inflammatory and anti-arthritic properties. Objectives: The research aimed to study the anti-cancer effect of SKN in diethylnitrosamine (DEN) and ferric nitrilotriacetate (Fe-NTA)-induced renal carcinoma in rats. Materials and Methods: The experimental animal groups consisted of Group I (Control), Group II (DEN + Fe-NTA), Group III (DEN + SKN), and Group IV (SKN alone). Retroperitoneal infusions were given for 24 weeks. Subsequently, tissues and blood samples were tested for biochemical, histopathologic, enzyme-linked immunosorbent assay, and western blot tests. Results: After 24 weeks, the antioxidant enzymes were found to increase in the SKN-treated groups. Histopathology revealed normal tissue morphology with a significantly reduced inflammatory response in SKN-treated animal groups compared to the control group. The serum levels of necrosis factor kappa B, PGE2, interleukin-1β, interleukin-6, and tumor necrosis factor-alpha were also down-regulated in the SKN-treated animal groups. The apoptotic proteins (Caspase-3, -9, and Bcl-2-associated X protein) were higher confirming SKN-induced apoptosis. Conclusion: Overall evidence suggests that SKN exhibits a reno-protective anti-cancer effect against DEN + Fe-NTA induced renal carcinoma in rats. Thus, SKN emerges as a therapeutic agent for kidney cancer therapy.