In a marine ecosystem, the most sensitive organisms to environmental changes, mainly to anthropic pressures, are fishes and invertebrates. Therefore, they are considered the ideal targets to indirectly evaluate the health of an entire ecosystem. Teleost fishes, particularly those that occupy the highest trophic levels, can accumulate toxic substances through their diet. In this study, we used two fish species with sedentary behavior and trophic habits, Diplodus sargus and Sarpa salpa, caught in two areas at different anthropic pressures divided into the Gulf of Naples (Na) and the Gulf of Salerno (Sa). This study aimed to correlate the pathological alterations in target organs in both species with known concentrations of polychlorinated biphenyls (PCBs) and heavy metals (lead and cadmium) to the expression of CYP1A1. Histological examination took into consideration circulatory disorders, increase in melanomacrophages (MMs) number, inflammation in kidney and hepatopancreas and gonadal stage maturation. Next, the pathological and morphological changes found were compared to immunohistochemical expression of CYP1A1 in the same samples. Chemical analysis of PCBs, based on 28, 52, 101, 138, 153, and 180 congeners, and heavy metals, were performed on hepatopancreas and muscle samples. Higher median values of PCBs concentration were detected in both species in the Salerno area (8.1 ng/g in Diplodus sargus muscles and 51.1 ng/g in Sarpa salpa hepatopancreas, respectively), although the values were consistently below the legal limits. No critical values were found for lead and cadmium. Therefore, we hypothesized that CYP1A1 and pathological alterations were more expressed in fish from Salerno area. The pathological changes showed a statistically significant difference in inflammation of the kidneys (p < 0.0001) between S. salpa of both Gulfs. In addition, we found a statistically significant difference in the assessment of the increase in MMs/MMCs (p = 0.0384) and circulation disorders (p = 0.0325) of hepatopancreas in D. sargus of both Gulfs. As not all the variables considered showed statistical significance, the analysis of the results does not fully support the correlation between the highest levels of contaminants found in the Salerno area and the expression of CYP1A1. Our data could be a starting point for future studies to better correlate the role of CYP1A1 to pollutants, considering this is the first study involving two of the most common species in the Mediterranean Sea. Thus, future studies could include other species to improve and increase records.