This study evaluated graded dietary doses of Saccharomyces cerevisiae postbiotic (0, 1.25, 2.5 and 5 g kg⁻¹) on growth, feed utilization, serum biochemistry, expression of IGF-1, SOD2, IL-1β, IL-10 and IgM, and resistance to Fusarium oxysporum in Nile tilapia (Oreochromis niloticus; 35.1 ± 0.9 g) after 30 and 60 days of feeding. Although the 5 g Kg⁻¹ inclusion significantly increased WG (59.4 ± 0.9) and SGR (1.5 ± 0.0) and decreased FCR (0.8 ± 0.0), significant positive effects on multiple endpoints were also recorded at 1.25 and 2.5 g/kg. Serum total protein and globulin rose with increasing dose and feeding duration, while albumin showed limited change, lowering the A/G ratio. AST remained unchanged. Creatinine and glucose declined with postbiotic supplementation; the glucose reduction effect was dose-dependent, whereas creatinine was unaffected by feeding duration. The highest gene expression of hepatic IGF-1, SOD2, IL-1β, and IL-10 and splenic IL-1β, IL-10, and IgM was in T3 at both checkpoints; however, the highest gene expression of intestinal IL-1β, IL-10, and IgM expression was in T1 at both time points. The pathogenicity experiment showed a significant survival against F. oxysporum (p < 0.0001) compared to controls. The results suggested that dietary S. cerevisiae postbiotic improved growth, biochemical and molecular responses, and survival of Nile tilapia against F. oxysporum.