Currently, the number of imaging and interventional procedures that use contrast agents (CAs) is gradually increasing. Contrast-induced nephropathy (CIN) is the most important CA-related complication. Oxidative stress plays a significant role in its pathophysiology. Lycopene (LPN) is a natural substance with strong antioxidant capacity. The present study aimed to investigate the potential preventive effects of LPN against CIN. In total, 28 male Wistar albino rats were divided into 4 groups with 7 rats in each group; the groups include normal control group, LPN only group at a dose of 4 mg/kg/day for 10 days, CIN group by administering 10 mg/kg furosemide IM + 10 mg/kg indomethacin IP + 10 ml/kg iomeprol IV following 24-h dehydration, and CIN + LPN group. There were statistically significant increase in urea, creatinine, and malondialdehyde levels (p < 0.001, for all) but a significant decrease in glutathione, superoxide dismutase, catalase, and glutathione peroxidase levels (p < 0.001, for all) in the CIN group compared with the control group. On histological examination, a significant increase of infiltrated inflammatory cells and necrotic degenerative changes were observed in the CIN group and the immunohistochemical examination revealed a significant increase in inflammation (inducible nitric oxide synthase), autophagy (LC3/B), and apoptosis (cleaved caspase 3) in the CIN group compared with the control group (p < 0.05, for all). Significant improvements in these unfavorable parameters were observed with CIN + LPN group compared with the CIN only group. In conclusion, the favorable effects of LPN as an anti-inflammatory, antiautophagic, and antiapoptotic agent in an experimental model of CIN have been demonstrated.