Cymothoid isopods cause serious infestations in fish that may adversely affect the aquaculture. Current study targeted investigating the enormous infestation of European sea bass Dicentrarchus labrax with cymothoid isopod, Nerocila species in a marine fish farm at Kafr El Sheikh Governorate, Egypt; accompanied with trials for treatment with malathion 57% at 0.15 and 0.30 mg/L concentrations and evaluation of the immune and antioxidants responses. For this purpose, 450 D. labrax were randomly collected alive during April 2020 and thoroughly examined for detection of external parasites. Malathion 57% treatment trial was carried out. Blood and tissue samples were collected from infested fish at zero-day (before malathion treatment) and at 24hrs, 48hrs, 3rd day, 4th day and 5th day (after malathion treatment). Isopods collected from infested fish were identified as N. orbigny and fish's external body surface and gills were the predilection sites. Both malathion concentrations were effective in eradicating N. orbigny and decreasing the isopod prevalence from 100 to 0% at the 5th day sampling point. Infested fish revealed improved hematological parameters (Erythrocyte counts, hemoglobin, and hematocrit readings), however leucocyte and differential cells counts showed significant decrease in infested fish. Immunological parameters (Lysozyme and IgM activities) decreased, but nitric oxide increased by time after malathion application. Nerocila is considered serious parasite in aquaculture that negatively affects fish's immune and antioxidative responses; and malathion denoted as a promising treatment to control N. orbigny in infested D. labrax.