: Contrast-induced nephropathy (CIN) is the third cause of hospital-acquired acute kidney injury. The CIN prophylactic strategies adopted to date, although not highly efficient, are mostly based on antioxidant activity and hydration therapy. This study was designed and conducted to evaluate crocin’s efficacy in the prevention of CIN in chronic kidney disease (CKD) patients undergoing coronary angiography/angioplasty. In this randomized clinical trial, a total of 110 eligible CKD stage 3 patients requiring contrast agent administration for coronary angiography/angioplasty were enrolled and randomly assigned to either crocin (n = 57) or control (n = 53) group. The patients in both groups received standard hydration therapy; nevertheless, in the crocin group, the patients were also orally administered three consecutive oral doses of 30 mg crocin tablets 1 day before up to 1 day after contrast media (CM) exposure. The primary endpoint was CIN incidence defined as an increase in serum creatinine (SrCr) level by ≥ 0.3 mg/dL or any change in urinary neutrophil gelatinase-associated lipocalin (NGAL) from the baseline within 48 hours of CM exposure. During 4 months, 130 patients were recruited. The mean age of the patients was 65.62 ± 9.05 years, and the majority of them were male (64.54%). The SrCr in the crocin group did not significantly increase within 48 hours of angiography/angioplasty. The changes in the urinary NGAL level were not significant in both groups. The CIN incidence was significantly lower in the crocin group than in the control group (1.75% and 13.2%; P = 0.028). Crocin administration plays an important nephron-protective role in the prevention of CIN.