The influences of Boswellia serrata resin extract (BSRE) as a feed additive on the growth performance, immune response, antioxidant status, and disease resistance of Nile tilapia, Oreochromis niloticus L. were assessed. One hundred-forty four fingerlings (initial weight: 21.82 ± 0.48 g) were randomly allotted into four groups with three replicates where they were fed on one of four treatments with four levels of Boswellia serrata resin extract 0, 5, 10, or 15 g kg−1, BSRE0, BSRE5, BSRE10, BSRE15, respectively for eight weeks. After the end of the feeding trial, the fish were challenged with Staphylococcus aureus, and mortalities were noted. The final body weight, total body weight gain, and the total feed intake were quadratically increased in BSRE5 treatment (p < 0.01). The protein productive efficiency (PPE) was linearly and quadratically increased in all BSRE supplemented treatments (p < 0.01). Dietary addition of BSRE raised the fish crude protein content and reduced the fat content in a level-dependent manner (p < 0.01). The ash content was raised in the BSRE15 group (p < 0.01). Dietary BSRE supplementation decreased the serum levels of glucose, total cholesterol, triglycerides, and nitric oxide. It increased the serum levels of total protein, albumin, total globulins, α1 globulin, α2 globulin, ß globulin, ɣ globulin, Catalase, and SOD (superoxide dismutase) activity, GSH (reduced glutathione), lysozyme activity, and MPO (myeloperoxidase) in a level-dependent manner (p < 0.05). The BSRE15 diet increased the serum level of ALT (alanine aminotransferase) and decreased creatinine serum level (p < 0.05). Dietary BSRE supplementation increased the relative percentage of survival % (RPS) of S. aureus challenged fish. The histoarchitecture of the gills and kidney was normal in the BSRE5 treatment and moderately changed in BSRE10 and BSRE15 treatments. The splenic lymphoid elements were more prevalent, and the melano-macrophage centers (MMC) were mild to somewhat activated in BSRE supplemented treatments. Dietary BSRE supplementation improved the intestinal histomorphology. It can be concluded that BSRE addition can enhance the antioxidant activity, immune status, and disease resistance of O. niloticus to S. aureus infection. The level of 5 g kg−1 BSRE can improve fish growth without causing harmful effects on fish health. The highest levels of BSRE are not recommended as they badly affected the histoarchitecture of many vital organs.