Lepidium sativum (LS) is an annual fast-growing herb that is now cultivated worldwide. It has been used for a long time as a traditional way in curing various diseases due to its different pharmacological properties. However, excess use of alternative medicine without medical supervision could lead to reverse toxic effect. Therefore, the present study aimed to evaluate the cytotoxic, genotoxic and mutagenic effect of oral administration of excess LS seeds aqueous extract in vivo. Animals were segregated into six groups; negative control, LS (200mg/kg), LS (400mg/kg), and LS (800mg/kg) daily administration for two consecutive weeks and LS (200mg/kg), and LS (400mg/kg) day by day administration for three consecutive weeks. Results show that high doses of LS, especially for daily schedule, increases mortality rate, leads to animal weakness, hair loss and abdominal bloating. In addition, LS administration distorts colon, liver, kidney and testis tissue in a dose dependent manner. Also, daily treatment increases cytotoxicity and genotoxicity of bone marrow cells detected by micronucleus assay and increases sperm abnormalities. Surprisingly, the present study records point of mutation in exon 5 of P53 gene in colon and liver tissue using SSCP assay. In conclusion, LS seeds extract is toxic in high dose administration for daily treatment and should be used in a therapeutic dose with no excess under medical supervision.