The endemic, green-lipped mussel (Perna canaliculus), trademarked as Greenshell™ mussel, contributes most to the New Zealand aquaculture industry based on tonnage and export value. Research on mussel immunity is motivated greatly by economical and biosecurity necessities. Indeed, mussel aquaculture is threatened by pathogenic micro-organisms and environmental stressors. As such there is a need to understand the mechanisms that drive mussel immune responses and the associated interactions with the environment. Specifically, this review (1) analyses the existing immunological studies conducted on P. canaliculus, (2) evaluates the literature pertaining to mussel immunity at the cellular and humoral levels, (3) identifies and discusses pathogens that are relevant to P. canaliculus, (4) focuses on the virulent factors employed by mussel pathogens likely to induce diseases, (5) provides a comprehensive analysis of the response mechanisms employed by mussels to various stressors, and (6) explores omics applications and future perspectives in mussel immunology. Finally, this review highlights various strategies from immunological research, such as gene rearrangement, probiotics, immunostimulants, and selective breeding, promising to enhance mussel health and resilience in aquaculture. By exploring these immunological findings and their practical applications, this review contributes to sustainable mussel aquaculture, improving productivity and disease management in the industry.