The red mullet (Mullus barbatus Linnaeus, 1758) is a keynote species for the Bulgarian Black Sea ecosystem and fisheries; nevertheless, existing knowledge on population status is very scarce. The present study was intended to assess the health status and adaptive potential of M. barbatus populations inhabiting the Bulgarian waters of the Black Sea. Our findings revealed that populations of M. barbatus are exposed to a variety of anthropogenic and environmental stressors. The species’ status was assessed using representative genetic, morphological, biochemical and chemical biomarkers from specimens obtained in the research area’s northern and southern regions. Based on mtDNA markers, genetic analysis revealed low haplotype and nucleotide diversity, typically observed in overexploited or “threatened” populations. Examining the morphology of the specimens revealed no discernible pattern of differentiation. Except for aluminium and chrome, metal and PAH concentrations in fish were below the regulatory thresholds. The specimens from the southern region ingested more microplastics than those from the northern region. The majority of specimens collected from the southern region also exhibited elevated levels of oxidative stress and decreased antioxidant defence, which can be interpreted as an early indication that they had reached the limits of their adaptive potential. Further research on the composite effects of the stressogenic environment on the Black Sea biota are critically needed, as well as the introduction of new indicators and thresholds at molecular and cellular levels for adequate monitoring of both the ecological state of the marine environment and its biota.