The current study investigates the hepatoprotective effect of Hyrtios aff. Erectus sponge extract against POPs intoxication on endogenous antioxidant enzymes and lipid peroxidation in mice liver tissue. In the present study, the mice BALB/C were assigned into four groups: group I: received saline subcutaneously for 7 days and served as negative control; group II: received subcutaneously for 7 days, 130.6 mg/100 g/b. w/day POPs mixture(mixture of PCB 28, PCB 52,, PCB 101, PCB 118, PCB 153, PCB 138 and PCB 180, alpha-Hexachlorocyclohexane, beta-Hexachloro-cyclohexane, gamma-hexachlorocyclohexane, Aldrin, O,P'-DDE, Dieldrin, P,p DDE, O,P DDD, Endrin, P,p DDD and P,pDDT were extracted from sediments collected from Lake Mariout), and served as induced group; group III: pretreated with Hyrtios aff. Erectus sponge extract for 7 days, as a protection dose and then treated with POPs as group II and served as protective group; and group IV: received i.p Hyrtios aff. Erectus sponge extract of dose 0.7 mg/100 g b.wt/day for 7 days and served as positive control. After 7 days (experimental period), mice were scarified and the liver was harvested for biochemical estimation. Significant reduction in lipid peroxidation (p < 0.002) was noticed compared to POPs-protected group. The antioxidant biomarkers levels were significantly increase as the hepatic GSH and GST increased by 69.9 and 89.9%, respectively. Such increase was accompanied by a decrease in tyrosine kinase activity by 59.82%, additionally remarkable histopathological changes in liver tissue indicate the protective effect of Hyrtios aff. Erectus sponge extract. The results of this study revealed that the Hyrtios aff. Erectus sponge extract has the potential to diminish the destructive effect of POPs intoxication through enhancement of the endogenous antioxidant status. The hepatoprotective activity of Hyrtios aff. Erectus sponge extract is mediated, by the antioxidant effect of its active constituents. The active constituents of Hyrtios aff. Erectus sponge extract were identified by LC-MS/MS.