Toxin and drug-induced nephrotoxicity (DIN) account for about 25% of all acute kidney injury cases and are associated with morbidity and increased utilization of healthcare services. No approved preventive compound is available for DIN. Saffron (Crocus sativus) has important biological properties like antioxidant and anti-inflammatory effects. The protective effects of saffron and its main constituents in different tissues including the brain, heart, liver, kidney, and lung have been confirmed against some toxic materials or drugs in animal studies. This review covers all aspects of saffron’s preventive and therapeutic effects against toxins and DIN including proposed mechanism of action, dosing schedule, and effects on renal biomarkers and histological changes. PubMed, Embase, Scopus, and Web of Science databases were searched by these search terms: “saffron” OR “Crocus sativus” OR “crocetin” OR “crocin “OR “safranal” AND “Drug induced nephrotoxicity” OR “Renal Injury” OR “Kidney Injury” OR “Nephrotoxicity”. All 25 relevant in vitro and in vivo studies up to the date of publication were included. Promising protective effects were reported particularly on aminoglycosides, cisplatin, and ethanol. Saffron and its constituents significantly prevented biochemical and histopathological changes, mediating via antioxidant, anti-apoptosis, and anti-inflammatory effects. Despite success in animal models, no human study is available in this field and further well-designed clinical trials are necessary for better judgment.