2-Butoxyethanol (2-BE) is a clear colorless liquid that smells like ether. It is used as a solvent in spray lacquers, varnishes, varnish removers, herbicides, liquid soaps, cosmetics, industrial and household cleaners, and dry-cleaning compounds. 2-BE causes cellular damage via formation of reactive oxygen species. Acacia nilotica (A.nilotica) leaf extract exhibited significant antimutagenic and DNA-protective effects against oxidative damage due to the presence of alkaloids, volatile essential oils, phenols and phenolic glycosides; it is considered an excellent free radical scavenging antioxidant owing to the high number of hydroxyl groups. Silymarin (SIL) is a standardized mixture of antioxidant flavonolignans (silybin and silibinin).     Silybum marianum (Milk thistle) family Asteraceae is an ancient medicinal plant from which SIL is extracted. It is a free radical scavenger and a membrane stabilizer that prevents lipid peroxidation. In the present study, we investigated the effects of extracts of A.nilotica leaves and SIL on the toxicity of 2-BE. Materials and Methods: 2-BE was given orally to male albino mice for 28 days at dose (450μl/kg b.wt).  A. nilotica leaf extract (25 mg/kg b.wt) was dissolved in water and was administered orally for 14 days prior to 28 days treatment of 2-BE and during the 28 days. Also SIL (20 mg/kg b.wt) was administered orally for 14 days prior to 28 days treatment of 2BE and during the 28 days.   Result: In the present work, genotoxic effects were induced by 2-BE through oral administration, and the protective effect of A. nilotica and SIL are studied. 2-BE induced a significant increase in the structural as well as numerical chromosomal aberrations. The frequency of chromosomal aberrations showed significant decrease when mice treated with A. nilotica extract and SIL. Also, there were significant increases in micronuclei. A. nilotica extract and SIL administration significant decreases micronuclei induced by 2-BE. However 2-BE induced a significant decrease in mitotic index. Administration of both A. nilotica extract and SIL significant increase mitotic index in mice treated with 2-BE. Exposure of mice to 2-BE caused significant changes in the  hematological paramters as well as significant increases in the activities of serum enzymes alanine aminotransferases (ALAT), aspartate aminotransferases (ASAT) and alkaline phosphatase (ALP). Also, 2-BE induced a significant decrease in the content of liver reduced glutathione (GSH), however, induced a significant increase in the level of hepatic lipid peroxidation end product (MDA) of male mice. Co-administration of both A. nilotica extract and SIL to 2-BE-intoxicated mice ameliorated the above-mentioned parameters. Conclusion: 2-BE induced mutagenic and liver injury in male mice. A.nilotica and SIL are found to reduce the percentage of chromosomal aberration and micronuclei cells as they are a powerful antioxidant, they are able to scavenger reactive oxygen species (free radicals) formed by 2-BE in the cells, these free radicals damage DNA and hence cause defects in the chromosomes. A. nilotica extract and SIL could be used as a protective agent against mutagenic and hepatic injuries resulting from 2-BE. The protective action ofSILis more effective than A. nilotica.