Protein-protein interactions (PPIs) play integral roles in a wide range of biological processes that regulate the overall growth, development, physiology and disease in living organisms. With the advancement of high-throughput sequencing technologies, increasing numbers of PPI networks are being predicted and annotated, and these contribute greatly towards the understanding of pathogenesis and the discovery of novel drug targets for the treatment of diseases. The use of this tool is gaining popularity in the identification, understanding and treatment of diseases in humans and plants. Due to the importance of aquaculture in tackling the global food crisis by producing cheap and high-quality protein source, the maintenance of the overall health status of aquaculture species is essential. With the increasing omics data on aquaculture species, the PPI network is an emerging tool for fish health maintenance. In this review, we first introduce the concept of PPI network, how they are discovered and their general application. Then, the current status of aquaculture and disease in aquaculture are discussed. The different applications of PPI network in aquaculture fish disease management such as biomarker identification, mechanism prediction, understanding of host-pathogen interaction, understanding of pathogen co-infection interaction, and potential development of vaccines and treatments are subsequently highlighted. It is hoped that this emerging tool-PPI networkwould deepen our understanding of the pathogenesis of various diseases and hasten the prevention and treatment processes in aquaculture species.