The innate immunity of invertebrates serves as a critical trait that provides a valuable foundation for studying the common biological responses to environmental changes. With the exponential growth of the human population, the demand for protein has soared, leading to the intensification of aquaculture. Regrettably, this intensification has resulted in the overuse of antibiotics and chemotherapeutics, which have led to the emergence of resistant microbes or superbugs. In this regard, biofloc technology (BFT) emerges as a promising strategy for disease management in aquaculture. By harnessing the power of antibiotics, probiotics, and prebiotics, BFT offers a sustainable and eco-friendly approach that can help mitigate the negative impacts of harmful chemicals. By adopting this innovative technology, we can enhance the immunity and promote the health of aquatic organisms, thereby ensuring the long-term viability of the aquaculture industry. Using a proper carbon to nitrogen ratio, normally adding an external carbon source, BFT recycles waste in culture system with no water exchange. Heterotrophic bacteria grow along with other key microbes in the culture water. Heterotrophs play a major role in assimilating ammonia from feed and fecal waste, crucial pathway to form suspended microbial aggregates (known as ‘biofloc’); while chemoautotrophs (e.g. nitrifying bacteria) oxidize ammonia into nitrite, and nitrite into nitrate promoting a healthy farming conditions. By using a highly aerated media and an organic substrates that contain carbon and nitrogen, protein-rich microbes are able to flocculate in culture water. Several types of microorganisms and their cell components have been studied and applied to aquatic animals as probiotics or immunostimulants (lipopolysaccharide, peptidoglycan, and 1-glucans) to enhance their innate immunity and antioxidant status, thereby enhancing their resistance to disease. In recent years, many studies have been conducted on the application of BFT for different farmed aquatic species and it has been observed as a promising method for the development of sustainable aquaculture, especially due to less use of water, increased productivity and biosecurity, but also an enhancement of the health status of several aquaculture species. This review analyses the immune status, antioxidant activity, blood and biochemical parameters, and level of resistance against pathogenic agents of aquatic animals farmed in BFT systems. This manuscript aims to gather and showcase the scientific evidences related to biofloc as a ‘health promoter’ in a unique document for the industry and academia.