Pollution by waste landfill leachate has prompted a number of studies on the toxic and potential health effects. This study assessed the genotoxicity of a municipal sludge leachate (MSL) in the somatic tissues (blood and bone marrow) and organs (liver, kidney, and spleen) of mice using the alkaline Comet assay. The possible cause of DNA damage via the study of antioxidant system (lipid peroxidation [LPO]; catalase [CAT]; reduced glutathione [GSH]; and superoxide dismutase [SOD]) responses in mouse liver was also investigated. Different concentrations (2.5%, 5%, 10%, and 15%) of the leachate were administered intraperitoneally for 5 consecutive days to male Swiss albino mice (4 mice/group). A significant (p < 0.05) increase in DNA damage in organs and tissues of treated mice compared to the negative control was observed as evident from the Comet assay parameters: olive tail moment (OTM, arbitrary units) and tail DNA (%). Bone marrow showed maximum DNA damage followed by liver > spleen > kidney > blood as evident by the OTM. A significant increase (p < 0.05) in the level of antioxidant enzymes (CAT and SOD) and LPO with a concurrent decrease in GSH in the liver of treated mice was also observed. Our finding demonstrates that the MSL induces DNA damage in the somatic tissues and organs of mouse as well as induces oxidative stress in the liver. These tissues and organs may be the potential targets in animal and human populations exposed to MSL. This is of relevance to public health; as such exposure could lead to adverse health effects via systemic genotoxicity.