Aquafeed quality is the most critical factor for aquaculture sustainability. However, limitations of traditional feed ingredients such as fishmeal (FM) need alternative strategies to ensure the nutritional requirements for aquatic animals. In this trial, four test diets were formulated (2 × 2 factorial design), where FM was incorporated in two diets at 10% with or without Saccharomyces cerevisiae (SC) at 1 g/kg. At the same time, FM was replaced with yellow mealworm (Tenebrio molitor) meal (TM) with or without SC at 1 g/kg. The growth performance indices (final weight, weight gain, and SGR), and the feed utilization indices (FCR and PER) were markedly affected by the protein source (FM or TM) and dietary SC (P < 0.05). The protein source (FM or TM) significantly (P < 0.05) affected the whole-body protein and lipid contents, while the moisture and ash contents were unaffected (P > 0.05) by TM or SC. The growth of the intestinal villi showed a marked increase in both height and branching in the treated groups with SC along the whole length of the intestine. Furthermore, the immune cell infiltration was prominent near the intestinal crypts of the middle intestinal segments in the supplemented groups by SC. Dietary TM and SC revealed improved hepatic parenchyma in the liver tissue better than other groups. The hematological indices, including hemoglobulin, hematocrit, red blood cells, and white blood cells, were markedly affected by dietary SC (P < 0.05). The lysozyme activity and phagocytic index were markedly affected by dietary SC, while phagocytic activity was affected by dietary TM (P < 0.05). The catalase, glutathione peroxidase, and malondialdehyde were markedly affected by the interaction between dietary protein source and SC, while superoxide dismutase was affected by dietary SC (P < 0.05). In conclusion, adding SC could enhance the utilization of TM by Nile tilapia with positive effects on the intestinal and liver histological features and the immune and antioxidative responses.