<p>This research aimed to assess the impact of integrating synbiotic (A-Pro Aqua®, SYN; 0.05 and 0.1%) and hydrolyzed yeast extract (Nutri Yeast-Aq®, HYE; 0.05 and 0.1%) as a factorial experiment 2 × 2 in a completel randomized design in the diet on growth performance, hemato-immunulogical responses, and digestive enzyme activities of Nile tilapia (<i>Oreochromis niloticus</i>) fry with intial weight 4 ± 0.2&#xa0;g for 63&#xa0;days. Three hundred fish were stocked in fifteen 120-L glass containers (20 fish per each unit) and fed with five diets containing control diet, 0.05% synbiotic + 0.1% yeast, 0.05% synbiotic + 0.05% yeast, 0.1% synbiotic + 0.1% yeast, and 0.1% synbiotic + 0.05% yeast. The findings indicated that elevated SYN and HYE levels significantly (<i>P</i> &lt; 0.05) increased final weight, specific growth rate, volountary feed intake, survival rate, protein productive value, and protein efficiency ratio. Additionally, higher SYN and HYE levels resulted in a significant decrease in feed conversion ratio and hepatosomatic index (<i>P</i> &lt; 0.05), while the activities of digestive enzymes such as protease, lipase, and amylase were considerably increased (<i>P</i> &lt; 0.05). The synergistic application of SYN and HYE in the diet markedly enhanced alternative complement activity and triiodothyronine, immunoglubolin, and lysozyme concentrations in the plasma of test fish (<i>P</i> &lt; 0.05). Moreover, the dietary supplementation SYN and HYE significantly elevated high-density lipoprotein concentation in the plasma of test fish while concurrently reducing low-density lipoprotein, very low-density lipoprotein, and triglyceride concentrations (<i>P</i> &lt; 0.05). In summary, based on the growth parameters and hemato-immunological responses, dietary supplementation with 0.1% SYN in conjunction with 0.1% HYE was recommended.</p>