The current study is aimed at determining the preventive effects of hesperidin against death, weight changes, cellular damage, and oxidative stress in mice induced by n-ethyl-n-nitrosourea as a chronic lymphocytic leukemia (CLL) model. Female mice were pretreated with hesperidin (20 mg/kg, intraperitoneally, daily for 30 days). Next, the animals received a single intraperitoneal injection of 80 mg/kg ENU on the 30th. Changes in weight and mortality were monitored for 120 days, and then the animals were sacrificed and parameters such as reactive oxygen species (ROS), mitochondrial dysfunction, lysosomal membrane integrity, oxidized/reduced glutathione (GSH/GSSG), and malondialdehyde (MDA) were analyzed in isolated lymphocytes. Hesperidin significantly increases the survival of mice up to 86% and delay in death time and prevents weight changes after exposure to ENU. Also, hesperidin improved cellular toxicity parameters such as ROS formation, MMP collapse, lysosomal membrane destabilization, and lipid peroxidation in isolated lymphocytes. These results promisingly showed that pretreatment with hesperidin increases delay in death time and reduces mortality cellular toxicities consistent with the carcinogenicity of alkylating compounds. This study confirms that the consumption of hesperidin and citrus most likely inhibits alkylating agents-induced carcinogenicity and toxicity.