One of the most significant bacterial diseases affecting the Nile tilapia is streptococcus, which has a significant negative impact on the global economy. As a result, vaccination is seen to be the best strategy for controlling bacterial disease in farmed fish. The objective of the current study was to assess the effects of formalin and autoclaved polyvalent vaccinations on immunological responses, oxidative stress biomarkers, antioxidant defense, and streptococcal protection in the Nile tilapia. Healthy fish (30±5g) were intraperitoneally vaccinated with 0.1ml of polyvalent vaccine, containing either formalin or autoclaved inactivated streptococcus agalactiae, streptococcus iniae and lactococcus garvieae, while the control group was injected with sterile saline. Serum samples were withdrawn 14 days post-immunization to assess immunoglobulin M (IgM), lysozyme activity (LYZO), alkaline phosphatase (AKP) and acid phosphatase (ACP).  In addition, oxidative stress biomarkers [malondialdehyde (MDA), nitric oxide (NO)], hepatic antioxidant activities [superoxide dismutase (SOD), catalase (CAT), glutathione reductase (GR), glutathione peroxidase (GPx)] were recorded. All groups were separately challenged by virulent strains of S. agalactiae, S. iniae and L. garvieae at the end of the immunization period (14 days). The results showed that IgM level and LYZO, AKP and SOD activities were significantly increased in both vaccinated groups, compared to the control group. The relative percent survival of the immunized Nile tilapia varied from 88.8- 94.0%. These results confirmed that both polyvalent formalin and autoclaved inactivated vaccine boost immune response, antioxidant activity and confer an excellent protective effect against streptococcal infection in the Nile tilapia.