For more than a century, bacterial infections caused by Vibrio spp. have affected various species of mussels around the world, with limited insights into the responses implemented by mussels against these infections. A combination of chemical analyses and carefully selected biological endpoints from haemolymph and tissues can be used to identify the welfare status of mussels and potentially protect aquatic ecosystems from catastrophic health threats. Recent developments in biomarker identification tools, such as omics and bioinformatics, have been successfully applied to evaluate the effect of environmental pollutants and other chemicals on mussels. However, the application of biomarkers to assess mussel health is limited. This review describes the available scientific literature on biomarker research for Vibrio-mussel interactions, and those aspects related to mussel health and disease assessment, grouped as biomarkers of exposure, effects, and susceptibility. From the review, it is clear that when integrated biomarkers are used, they can provide a deeper understanding of the relative health and potential susceptibility of mussels for better management practices. Furthermore, health biomarker data can be used to build resilience in mussels against climate change conditions, strengthen biosecurity management programs, improve farming and processing efficiency, and add value in terms of market-desirable traits. These data hold promise for advancing sustainability efforts within the aquaculture industry. Graphical abstract: (Figure presented.)