Monogeneans induce significant economic losses and pose a danger to the sustainability of aquaculture. Using disinfectant medication has detrimental effects on fish health. Therefore, it is essential to look for efficient safe alternatives for the chemical medication. The present study exhibits that tea tree (Melaleuca alternifolia) essential oil (MAO) might provide a promising anti-parasitic alternative for conventional anthelmintics to treat gill monogeneans (Dactylogyrus spp) infection in African catfish. The in vitro anthelmintic capability of different concentrations of MAO (10, 20, 30, and 40 mg/L) was tested for 8 h. An in vivo assay was applied for ten days, where fish (n=200; 80.37±5.98 g) were assigned at random into four groups in five replicates (control, MAO, Dactylogyrus spp, and MAO + Dactylogyrus spp). A concentration of 40 mg/L of MAO was used as a therapeutic dose. The outcomes of the in vitro assay demonstrated that the survival of Dactylogyrus spp was inversely correlated with the concentrations of MAO. In vivo, the parasitic intensity and vitality were significantly reduced by MAO bath treatment and inversely correlated with the time of exposure. Dactylogyrus spp infection induced significant lowering (P < 0.05) in hematological and protein profiles (red and white blood cells, hemoglobin, packed cell volume %, total protein, albumin, and globulin) and immune-antioxidant responses (lysozyme, nitric oxide, complement 3, catalase, reduced glutathione, and total antioxidant capacity). Moreover, an apparent rise (P < 0.05) in the levels of hepato-renal function variables (aspartate aminotransferase, alanine aminotransferase, and creatinine) and stress biomarker (cortisol) with were the consequences of Dactylogyrus spp infection. Dactylogyrus spp-infected fish exhibited the highest mortality rate (48%) and with marked histopathological changes (hyperplasia, inflammation, hemorrhages, and sloughing with inflammatory cells infiltrates) in the gills with an up-regulated apoptotic marker (caspase-3). Interestingly, treatment of Dactylogyrus spp-infected fish with MAO improved these biomarkers and decreased the mortality rate (18%) with an observable regeneration of the histopathological alterations. Overall, these findings suggest that MAO as an aqueous addition can protect fish from the harmful effects of Dactylogyrus spp and make a promising anti-parasitic agent.