Sixty days feeding trial was carried out to investigate the supplemental effects of dietary phytobiotic mixture composed of Spirulina platensis powder (SP) and Garlic powder (GP) on the growth performance, intestinal morphometry, and immune responses of Nile tilapia Oreochromis niloticus. A total of 240 cultured O. niloticus (41.4 ± 0.09 g) were randomly divided into four experimental groups (three replicate/group), fed on basal diets contain 0% (control), 1% (SP), 0.5% (GP), or a combination of both (SP + GP). Fish group fed on phytobiotic mixture showed significant improvements in its feed intake, live weight gain, specific growth rate, feed conversion ratio and protein efficiency ratio (p<0.05), associated with a healthy gut, compared to non-supplemented control. Dietary supplementation of phytobiotics appeared to stimulate the humoral and cellular innate immunity. Fish group that were fed on phytobiotic mixture revealed up-regulation in some immune related genes; TNF-α and liver hepcidin as well as it exhibited the least cumulative mortality % upon A. hydrophila infection. So we can conclude that dietary supplementation of garlic and Spirulina have been improved the growth performance, gut health, immune status and disease resistance in Nile tilapia.