Fusarium oxysporum is one of the systemic mycosis that affects fish. This study was designated to determine the pathogenicity of Fusarium oxysporum in Oreochromis niloticus with a clinical trial for treatment. Fusarium oxysporum isolated from naturally infected Oreochromis niloticus collected from different fish farms at different governorates in Egypt namely, El Fayum, kafr El-sheikh and Alexandria. Fish samples with a total number of 100 were collected during the period from May to October 2019. Microbial examination revealed infection with Fusarium oxysporum that was identified by molecular sequence analysis of the internal transcript spacer (ITS) region of their ribosomal RNA gene. The confirmed isolate of Fusarium oxysporum, was used in experimental infection to determine its Pathogenicity followed by a trial for treatment of clinically affected fish with Curcumin and H2o2. The clinical signs associated with experimental infection were exophthalmia, abnormal swimming behaviour, granuloma in different internal organs including gills, liver and spleen with enlargement of spleen and congestion of liver. Examination revealed severe pathological alteration gills, liver and spleen manifested by severe congestion of the central venous sinuses of the primary gill lamellae as well as the blood vessels of the secondary lamellae associated with lamellar edema , congestion of hepatoportal blood vessels and sinusoids associated with perivascular edema and presence of variable granulomas embedded in the splenic parenchyma . Curcumin and H2o2 showed a mild beneficial effect as a treatment for Fusarium oxysporum infection in cultured Oreochromis niloticus.