Ethnopharmacological Relevance: Leukemia, a cancer of the blood and bone marrow is responsible for about 222.000 deaths annually. The side effects of chemotherapy in leukemia treatment have necessitated the search for natural products especially medicinal plants as alternative therapy. Aim: This study surveyed common plants used for treating leukemia in Oyo state, Nigeria and assessed the anti-leukemic and anti-clastogenic activities of fractions of Nymphaea lotus. Methods: Semi-structured questionnaire (1000) was used to collect the ethnobotanical data among the traditional healers. Leukemia was induced in albino mice with 400 mg/kg body weight of benzene intraperitoneally. Aqueous extracts (120mg/kg/bw), fractions and 5-florouracil (25mg) was administered to mice of different groups. The anti-leukemic, anti-clastogenic, antioxidant, hepatoprotective activities and hematological parameters were determined. N. lotus was subjected to gas-chromatography mass spectroscopy analysis. Results: The ethnobotanical survey recorded 89 plant species with their local names and parts used in the traditional therapeutic preparations. Seven plants (Pistiastratiotes (2.5%), Nymphaea lotus (1.4%), Piper guineense (1.7%), Securinega virosa (2.5%), Calotropis procera (3.4%), Morinda lucida (2.5%) and Xylopia aethiopica (4.5%) with the highest frequency of citation were selected for anti-leukemic and anti-clastogenic screening. The aqueous extract of N. lotus and M. lucida displayed anti-leukemic potential. M. lucida and X. aethiopica improved the hematological parameters. Ethyl acetate fraction of N. lotus significantly (p<0.05) reduced the number of micronucleated polychromatic erythrocyte in the bone marrow and showed anti-leukemic activity. Fractions of N. lotus restored the hematological parameters and exhibited significant (p<0.05) antioxidant activity. Histological observation revealed improvement in the liver general cyto-architecture of mice treated with ethyl acetate and butanol fractions of N. lotus. Some known compounds were identified in ethyl acetate fraction of N. lotus. Conclusion: Most of the species tested had some anti-leukemic effect in mice, which to some extent supports their traditional inclusion in herbal preparations for treatment of leukemia. The study also identified potential anti-leukemic compounds in N. lotus extract. The study also identified potential anti-leukemic compounds in N. lotus extract.