Contrast medium (CM) is a chemical substance that is used for imaging anatomical boundaries and to explore normal and abnormal physiological findings; the use of CM was associated with kidney injury and acute renal failure. Melatonin (M) possesses antioxidant, anti-inflammatory, and antiapoptotic effects in addition to autophagy modulation. This study aimed to investigate the protective effect of M against contrast-induced nephropathy (CIN) and its impact on the crosstalk between inflammasome, apoptosis, and autophagy in CIN. Male albino rats received M (10, 20, and 40 mg/kg/day, intraperitoneally) for 3 days. One hour after the last administration, rats were subjected to CIN induction (10 mg/kg indomethacin, double doses of l-NAME 10 mg/kg, i.v., and meglumine diatrizoate 60% 6 mL/kg, i.v.). CIN-induced kidney damage was evidenced through elevated kidney function biomarkers and induced renal histopathological changes. Pretreatment with M caused a significant decrease in nephrotoxicity biomarkers and histopathological alterations. Moreover, CIN-induced oxidative stress, NLRP3 inflammasome, and apoptosis were attenuated by M. Furthermore, M modulates autophagy in CIN rats. M inhibits CIN-induced NLRP3-inflammasome activation and apoptosis as well as enhances autophagy.