Aquaculture is a growing sector of the food industry that actively tries to integrate scientific knowledge into its management strategies. Aquaculture faces several key challenges including the provision of high-quality nutritional sources that serve to address both quality and safety, thus transforming production and management strategies to integrate sustainable principles. Proteomics has been established as a powerful and unbiased instrument in environmental monitoring and risk assessment. Proteomics in aquaculture has been applied to address welfare, nutrition, health, environmental quality, and safety. In this review, we will focus on the proteomics-based method developed and implemented for its application to elucidate the key challenges that face the fish and seafood industries: quality and safety. The latest methodological developments in high-throughput proteomics and metaproteomics are seeing rapid integration into aquaculture research contributing to the common goal of offering high quality food production processes and environmental sustainability.