PUNICA granatum (Pg) is an edible fruit known as pomegranate, which is a rich source of polyphenolic compounds and has antioxidant activity. Many studies have been conducted on extracts of various parts of Pg which may have genotoxic effects. However, the purpose of the present study is to assess, for the first time, the radio-protective effect of Pg juice, the safest part of the fruit, against γ-irradiation-induced biochemical and cytogenetic damage in rats by modulating the lipid profile, and the esterases (acetylcholinesterase AchE, carboxylesterase CarE and paraoxonase PON) activity as biomarkers that provide information on the nervous system's integrity, metabolism, and anti-oxidative defenses respectively. Male rats were divided into six groups, group I is the control, group II received Pg juice (400 mg/kg/day) divided into two equal doses twice daily (with 12 h interval) for 30 days, group III and V received 4 Gy and 8 Gy of γ-radiation respectively, group IV and VI received Pg juice for 30 days before being irradiated with 4 and 8Gy of γ-radiation respectively. Radiation altered the levels of CarE and PON activity in plasma and liver, as well as plasma total cholesterol, triglycerides, high-density lipoprotein HDL, low-density lipoprotein LDL, and very low-density lipoprotein VLDL. In comparison to the control group, Pretreatment with Pg juice significantly improves these values and reduced DNA fragmentation significantly. It is possible to conclude that Pg juice protects against ionizing irradiation, which causes biochemical and cytogenetic damage, by modulating anti-oxidative defenses and metabolism.