Nanotechnology offers a promising future for various applications in many disciplines and its progress positively influences more jobs, including remedies against diseases and biological and environmental controls. This chapter covers the substantial role of nanotechnology in sustaining a fish's immune defense system and consequently, increasing fish resistance and producing high-performing fish. We highlight the immune-modulatory properties of nano-materials in aquaculture, either through the activity of the nano-material itself or via synchronization with a nano-delivery route. Both metal and natural plant-based nano-materials are also addressed. They are categorized by distinctive properties including a wider area-to-volume ratio which enhances their utilization. Nowadays, there is extensive application of nanoparticles either in fish diets or via rearing water as their small (nano) size allows for their easy cellular passage, and inducing their promising effect.