Simple SummaryRabbit farming is increasingly requiring non-antibiotic alternatives to improve rabbit gut health to maintain high feeding efficiency and excellent production index. Thus, using a friendly alternative is an appropriate way to protect rabbits from pathogens while also enhancing their performance and welfare. Lysozyme, an enzyme derived from avian egg white, aids in nutrient digestion and absorption and provides protection against bacterial diseases while lowering pollutants’ excretion, such as ammonia. Thus, the aim of this study was to evaluate the effect of lysozyme supplementation in rabbits’ diets on growth performance, caecal fermentation, bacteria population, and blood constituents. The results demonstrated an improvement in rabbit performance, caecal fermentation, blood lipid profile, and antioxidant status due to an increase in beneficial bacteria in lysozyme-treated rabbits. Therefore, supplementing the rabbit diet with lysozyme up to 150 mg/kg is recommended.The effects of exogenous lysozyme supplementation (LYZ) on growth performance, caecal fermentation and microbiota, and blood characteristics were investigated in growing rabbits. A total of 420 growing male V-Line rabbits (30 d old; weighing 528 ± 16 g) were randomly divided into four groups of 105 rabbits each, and monitored for 42 days. Experimental groups included a control group (LYZ0) fed a basal diet without LYZ supplementation, and three treated groups fed the same basal diet supplemented with LYZ at 50, 100, and 150 mg/kg diet, respectively. The results showed a quadratic improvement in the final body weight, daily growth rate, FCR, and digestibility of DM, while the digestibility of OM, CP, EE, NDF, and ADF improved linearly when LYZ supplementation was increased. The dressing percentage increased quadratically when LYZ levels were increased in the rabbit diets. In rabbits fed LYZ diets, L. acidophilus counts increased linearly (p < 0.05) and L. cellobiosus, and Enterococcus sp. counts increased quadratically, whereas E. coli counts decreased. In the LYZ-supplemented groups, the caecal pH value and NH3-N concentration declined quadratically, whereas total VFA, acetic, and butyric acids increased. Total lipids decreased linearly, whilst triglycerides and cholesterol decreased quadratically with LYZ supplementation. Total antioxidant capacity, superoxide dismutase, glutathione S-transferase, and catalase increased quadratically, while malondialdehyde decreased linearly in the LYZ-supplemented groups. In conclusion, exogenous lysozyme administration improved rabbit growth performance and antioxidant status while lowering the blood lipid profile, altering the bacterial population, and regulating caecal fermentation. Therefore, LYZ up to 150 mg/kg can be used as a potential supplement in rabbit feed.