Objective: To evaluate the safety and the possible antimutagenic effect of the defatted aqueous ethanol extract and polysaccharide extract of Plantago albicans L. areal parts on the genotoxicity of the anticancer drug cyclophosphamide and to investigate the chemical constituents of these extracts. Methods: Two doses of each extract (10 and 15 mg/kg body weight) were administered orally to albino mice 7 d prior to treatment of cyclophosphamide (20 mg/kg body weight, i.p). Chromosomal aberration analysis and micronucleus test were performed. Phytochemical investigation of defatted aqueous ethanol extract was carried out through chromatographic tools, chemical and physical analysis to know the active constituents of these extracts. Results: Groups of mice administered with defatted aqueous ethanol extract and polysaccharide extract prior to cyclophosphamide treatment showed statistically significant reduction in the percentage of chromosomal aberrations and micronuclei in bone marrow cells in a dose-dependent manner. Defatted aqueous ethanol extract gave more effective protection in comparison with polysaccharide extract. Phytochemical investigation of defatted aqueous ethanol extract allowed isolation of gallic acid, methylgallate, tri, tetra, penta-galloyl-β-glucopyranoside, kaempferol-3-O-β-sophro pyranoside, quercetin-3-O-β-glucopyranoside-7-O-α-rhamnpyranoside, kaempferol and quercetin, for the first time from this species. Conclusions: The results of the present work demonstrated that Plantago albicans phytoconstituents play a protective role against genotoxicity of the drug cyclophosphamide.