The present study evaluated the pathogenicity, immunological, and oxidant/antioxidant responses againstSaprolegnia parasitica(S. parasitica) infection in Nile tilapia (Oreochromis niloticus). Three groups of Nile tilapia were assigned as the control group (no zoospores exposure). The other two groups were challenged by Saprolegnia zoospores; one was used for sampling, and the other for mortality monitoring. The study lasted 3 weeks and was sampled at three point times at 1, 2, and 3 weeks. Results showed thatS. parasiticazoospores were pathogenic to Nile tilapia, causing a cumulative mortality rate of 86.6%. Immunoglobulin M and C- reactive protein (IgM and CRP) levels showed a similar trend being significantly (P< 0.05,P< 0.001) higher in the infected group at weeks 1, 2, and 3, respectively, compared to the control group. Oxidant and antioxidant parameters in gills revealed that Malondialdehyde (MDA) level was significantly higher in the infected group compared to the control group. While catalase, glutathione peroxidase, and superoxide dismutase (CAT, GSH, and SOD) levels were significantly decreased in the infected group compared to the control group. Compared to the control, the tumor necrosis factor-α (TNF-α) gene was firmly upregulated in gill tissue at all-time points, particularly at day 14 post-infection. Meanwhile, Interleukin 1-β(IL-1 β) gene was significantly upregulated only at days 7 and 14 post-infection compared to control. Histopathological examination revealed destructive and degenerative changes in both skin and gills of experimentally infected Nile tilapia. Our findings suggest that Nile tilapia-S. parasiticainfection model was successful in better understanding of pathogenicity and host (fish)-pathogen (oomycete) interactions, where the induced oxidative stress and upregulation of particular immune biomarkers in response toS. parasiticainfection may play a crucial role in fish defense against oomycetes in fish.