For the purpose of biomonitoring, species that combine ecological and commercial importance may provide a link between ecological and human health risk. The common cuttlefish, Sepia officinalis, holds both characteristics in south-western Europe, albeit remaining unsurveyed in ecotoxicological studies. Cuttlefish collected from an impacted estuary in SW Portugal and a reference location off the coast were analysed for a battery of biomarker responses in the digestive gland and gills. The contrast to reference animals revealed that biomarker responses, especially those related to oxidative stress, were consistent with sediment contamination by PAHs, even in a situation that combines complex toxicant mixtures, moderate levels of contamination and high ecotoxicological diversity. However, environmental parameters related to the differences between shore and estuarine habitats should not be overruled. Also, digestive gland metallothionein retained significant specificity to metals even though previous studies in the area with clams and fish failed to trigger a conclusive response. The highest net differences in biomarker responses were detected in the gills, likely indicating higher sensitivity to environmental stressors. Still, the digestive gland responses were overall the most consistent with sediment contamination and effectively differentiated between estuarine industrial- and rural-impacted sites. The results indicate that S. officinalis may be a candidate to meet the European Union’s requirements for efficient biomonitoring programmes, with the additional importance of being cosmopolitan, abundant, commercially valuable and combining the molluscan biology that has been granting bivalves their high value for biomonitoring with foraging behaviour, thus better able to reflect anthropogenic stressors impacting a wider area than sedentary organisms. Nevertheless, further investigations in unpolluted sites are needed to better evaluate the background levels of biomarker responses in the species.