Zinc is one of the essential microelements for the metabolism of animals. Zinc nanoparticles may have higher bioavailability due to their low specific surface area, facilitating absorption by fish. The present study aimed to evaluate the effects of supplementation with different zinc-based products on the growth and health of Nile tilapia Oreochromis niloticus. Zinc, in different sizes (nanoparticles or bulk) and forms (inorganic or organic), were used as a supplement in the tilapia diet at a dose of 15 mg kg feed−1 for 60 days. At the end of the feeding trial, production performance, hemato-immunological parameters, activity of antioxidant system enzymes, exposure to Streptococcus agalactiae and zinc concentration in the muscle were examined. After the bacterial challenge, the mean corpuscular hemoglobin concentration (MCHC) significantly increased in the fish treated with organic zinc, inorganic nano zinc, and organic nano zinc, while in the control group (inorganic zinc), MCHC remained unchanged. Regarding defense cells, dietary inorganic nano zinc increased the number of basophils (1.50 ± 1.10) compared to organic zinc (0.80 ± 0.90). Lymphocyte count increased after the challenge only in the organic zinc treatments (bulk and nanoparticles). Neutrophils decreased in the control (inorganic zinc) (2.20 ± 1.70) and inorganic nano zinc (2.60 ± 2.70) treatments after the challenge. When compared before and after the bacterial challenge, the plasma antimicrobial titer significantly increased after the bacterial challenge in all treatments. No significant differences were observed for total proteins, enzymes (SOD and CAT), cumulative survival and zinc deposition on fillet. In conclusion, organic zinc in nanoparticles or bulk size increased Nile tilapia innate defense during bacterial infection. However, the other parameters evaluated were not affected by zinc particle size or form (organic or inorganic), indicating that further evaluations should be conducted with organic zinc in nanoparticles or bulk size in the tilapia diet.