The purpose of this research was to determine whether or not supplementing a diet with ethanolic roselle calyces extract (ER) had any effect on the rate of growth, intestinal morphometry, total carotene in skin and muscle, blood profile, immunity status, and the expression response of red tilapia. The ER was added to four experimental diets at 0% (0 g kg−1), 0.5% (5 g kg−1), 1% (10 g kg−1), and 2% (20 g kg−1), which were designated as ER0 (control group), ER0.5, ER1, and ER2, respectively. The results show that ER1 induced higher weights (final weight, weight gain, specific growth rate, and weight gain rate) and all ER groups had considerably (p < 0.05) decreased feed conversion rates (FCR) compared with the control diet. Histomorphometric examination of the intestinal villi absorptive capacity showed fish given ER, specifically ER1, had increased villus length, width, and goblet cells (p < 0.05). The best hematological and biochemical parameters (the antioxidant enzyme activity of superoxide dismutase and catalase, lysozyme activity, and WBCs count) were observed for 5 g kg−1 ER. In addition, diets supplemented with different levels of ER stimulated phagocytic activity (p < 0.05). Additionally, the highest total carotene content in skin and muscle was observed in ER0.5. The 0.5, 1, and 2% roselle extract diets induced upregulation of IGF-1, GHr, SOD, TNF-α, and LPL, whereas MSTN, HSP 70, and FAS were downregulated. In conclusion, dietary ER supplementations are advantageous for red tilapia because they improve immunological and growth-related parameters.