Our study proposed a promising anti-fungal therapy to control Saprolegnia spp. infection in Nile tilapia (Oreochromis niloticus). A Moringa oleifera synthesized silver nanoparticles (MS-AgNPs) showed an in vitro anti-fungal activity against Saprolegnia spp. with an inhibition zone of 18 mm. A total of 220 O. niloticus (45 ± 0.56 g) were used in this study. A preliminary investigation was conducted by using 100 fish for determining the safe dose of MS-AgNPs which was found to be 0.6 mg/L. Another 120 fish were divided into four groups; the first (control) and second groups (G1 and G2) were non-infected and exposed to 0 and 0.6 mg/L MS-AgNPs, respectively. The third and fourth groups (G3 and G4) were infected with Saprolegnia spp. (1.5 × 104 spores/L) and exposed to 0 and 0.6 mg/L MS-AgNPs, respectively. The experiment lasted for 7 days. The infection with Saprolegnia spp. induced immunosuppression expressed by a marked decrease in immunoglobulin M, nitric oxide, complement 3, and lysozyme activity, with a 41 % survival rate. Additionally, a marked decline in the values of hepatic and branchial antioxidant enzymes (superoxide dismutase and catalase) in addition to serum total antioxidant capacity and protein profile indices. In contrast, Saprolegnia spp. infection elevated hepatic and branchial malondialdehyde, hepatic function indicators, and stress biomarkers (cholesterol and triglyceride) with up-regulation of the pro-inflammatory cytokines (IL-1ß and TNF-α), and the anti-inflammatory cytokines (IL-10 and TGF-β). Histopathological findings of the gills and musculature of infected fish showed severe hyperplasia of the epithelial lining with a fusion of secondary lamellae and necrotic myocytes admixed with edema. Interestingly, treatment of the challenged fish with MS-AgNPs at a dose of 0.6 mg/L could improve these variables by enhancing the histological architecture. According to these findings, MS-AgNPs have an ameliorative effect against the harmful effects of Saprolegnia spp. infection on immune-antioxidant status and hepatic functions indices. Consequently, MS-AgNPs at a dose of 0.6 mg/L is a promising option for use in the control of Saprolegnia spp. infection in aquaculture. DOI: 10.1016/j.aqrep.2022.101318