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The stamens of Crocus sativus L., often discarded as floral waste, are rich in flavonoids and phenolics. This study investigated their toxicological safety, antigenotoxic potential, and molecular mechanisms of protection against cyclophosphamide (CP)-induced genotoxicity. Hydroethanolic and hydromethanolic extracts were prepared, and acute oral toxicity was assessed in mice following the Organization for Economic Co-operation and Development guideline 423. Genotoxicity and its amelioration were evaluated in rat and mouse leukocytes by employing the alkaline comet assay. Oxidative stress markers, including superoxide dismutase activity, as well as malondialdehyde and glutathione levels, in hepatic and renal tissues were quantified. In parallel, nine major metabolites were identified in the extracts and were molecularly docked with key enzymes involved in CP bioactivation (CYP2B6), aldehyde detoxification (ALDH1A1), DNA repair (OGG1), and oxidative stress regulation (Keap1-Kelch domain; Protein Data Bank ID: 7K2A). The extracts were non-toxic up to 4,000 mg/kg and did not exhibit any genotoxicity. Pre-treatment with extracts (200 mg/kg body weight) significantly attenuated CP-induced DNA damage and restored antioxidant enzyme levels. Docking results supported these observations: rutin demonstrated a high affinity for CYP2B6 (-11.2 kcal/mol) and favorable binding to 7K2A (-9.7 kcal/mol); catechin gallate bound tightly to ALDH1A1 (-10.0 kcal/mol) and OGG1 (-9.2 kcal/mol). These findings suggest reduced CP activation, but enhanced detoxification and DNA repair. In conclusion, the extracts of C. sativus stamens are safe and possess robust antioxidant and antigenotoxic properties, confirmed by molecular docking. These findings highlight their potential as natural protective agents against chemotherapy-induced genotoxicity.