This study investigated the benefits of yeast, Saccharomyces cerevisiae and/or garlic, Allium sativum supplementation in diets of Nile tilapia with regard to growth, antioxidant status, hepatic and intestinal histoarchitecture, expression of growth- and immune-related genes, and resistance to Aeromonas sobria infection. Fish (with an initial weight of 9.43 ± 0.08 g) were allocated to twelve hapas, organized into four triplicate treatment groups defined as control (no supplementation), yeast (4 g/kg diet), garlic (30 g/kg diet), and a mixture of both. This trial continued over a 60-day feeding period. Results revealed that combined treatment (yeast + garlic) demonstrated the most promising outcomes regarding growth, with significantly higher final body weights, weight gains, and specific growth rates compared to other groups. Moreover, this combination enhanced hepatic antioxidant status, as evidenced by elevated levels of reduced glutathione and activities of catalase and superoxide dismutase enzymes, reflecting improved defense against oxidative stress. Histological assessments of the livers and intestines demonstrated structural enhancements in yeast and garlic treatments, suggesting improvements in organ health. In comparison to the control, the gene expression analyses unveiled increased expression of growth-related (igf-1 and ghr1) and immune-related (il-10, lyz, and hep) genes in the test groups, indicating a possible reinforcement of the growth and immune responses. The combined treatment also showed the highest resistance to A. sobria infection, as evidenced by improved survival rates and lower mortality compared with the other groups. These findings highlight the benefits of a combination of both yeast and garlic as a dietary supplementation regimen. In conclusion, this study suggests that the combined treatment regimen could be considered an effective strategy to promote the health and productivity of Nile tilapia under production conditions.