Aeromonas veronii is a pathogenic bacterium associated with various diseases in aquaculture. However, few studies address the antibacterial activity using nanoparticles (NPs). Hence, the current study is innovative to evaluate the antibacterial efficacy of silica nanoparticles (SiNPs) against A. veronii infection in-vitro with a trial for treatment in-vivo. Primarily, we assessed the in-vitro antibacterial activity against A. veronii. Further, we investigated the hematological profile, immune-antioxidant response, and gene expression of African catfish (Clarias gariepinus) in response to SiNPs exposure and the A. veronii challenge. Fish (N = 120; weight: 90 ± 6.19 g) were distributed into four groups (30 fish/group) for a ten-days-treatment trial. The first (control) and second (SiNPs) groups were treated with 0 mg/L and 20 mg/L SiNPs in water, respectively. The third (A. veronii) and fourth (SiNPs + A. veronii) groups were treated with 0 mg/L and 20 mg/L SiNPs in water, respectively, and infected with A. veronii (1.5 × 107 CFU/mL). Results demonstrated that SiNPs displayed an in-vitro antibacterial activity against A. veronii with a 21 mm inhibitory zone. A. veronii infection caused a high mortality rate (56.67%) and substantial reductions in hematological indices and immune indicators [nitric oxide (NO) and immunoglobulin M (IgM)]. Additionally, marked decline in the level of antioxidants [superoxide dismutase (SOD), catalase (CAT), and reduced glutathione content (GSH)] as well as down-regulation in the immunerelated genes [interleukins (IL-1β and IL-8) and tumor necrosis factor-alpha (TNF-α)] and antioxidant-related genes [SOD1, glutathione peroxidase (GPx), and glutathione-S-transferase (GST)] were the consequences of A. veronii infection. Surprisingly, treatment of A. veronii-infected fish with SiNPs lessened the mortality rate, enhanced the blood picture, modulated the immune-antioxidant parameters, and resulted in gene up-regulation. Overall, this study encompasses the significant role of SiNPs, a new versatile tool for combating hematological, immuno-antioxidant alterations, and gene down-regulation induced by A. veronii infection and sustainable aquaculture production.