The evaluation of past and present anthropogenic impacts affecting the ecological quality status of transitional ecosystems is crucial from the perspective of protecting them from further deterioration, and to evaluate remediation and restoration measures. Contamination patterns of thick-lipped grey mullet from two Mediterranean coastal lagoons within a protected area in Italy were assessed and compared in order to evaluate their overall quality status and to collect information that can provide useful feedback on management choices aimed at enhancing environmental quality and biodiversity conservation. The quality status of the two lagoons was evaluated by an environmental assessment methodology based on indicators of direct and indirect human pressures, while a broad range of analyses were carried out to determine the presence and concentration of persistent organic pollutants (POPs) and metals in fish muscle tissue. A good quality status resulted for both lagoons, and an overall limited anthropogenic impact in the surrounding area. This could account for POPs and metal contamination levels found in mullet, although limited, and relating to their patterns. The overlap of results achieved with the two evaluation approaches can provide support for management choices in Mediterranean lagoon environments, especially for those committed to the protection and conservation of biodiversity.