Multiple anthropogenic activities present along coastal environments may affect the health status of aquatic ecosystems. In this study, specimens of European sea bass (Dicentrarchus labrax) were exposed for 30 days to highly contaminated sediment collected from the industrial area between Augusta and Priolo (Syracuse, Italy), defined as the most mercury polluted site in the Mediterranean. The aim was to evaluate the responses of juvenile D. labrax to highly contaminated sediments, particularly enriched in Hg, in order to enhance the scarce knowledge on the potential compensatory mechanisms developed by organisms under severe stress conditions. Apoptotic and proliferative activities [cell turnover: Proliferating Cell Nuclear Antigen (PCNA) and FAS Ligand (FasL)], onset of hypoxic condition [hypoxia: Hypoxia Inducibile Factor-1α (HIF-1α)], and changes in the neuroendocrine control mechanisms [neurotransmission: Tyrosine Hydroxylase (TH), Choline Acetyltransferase (ChAT), Acetylcholinesterase (AChE), 5-Hydroxytryptamine (5-HT) and 5-Hydroxytryptamine receptor 3 (5-HT3)] were investigated in sea bass gill tissues. In the specimens exposed to the polluted sediment, the occurrence of altered cell turnover may result in impaired gas exchange that leads to a condition of "functional hypoxia". Changes in neurotransmission pathways were also observed, suggesting a remodeling process as an adaptive response to increase the O2-carrying capacity and restore the normal physiological conditions of the gills. Overall, these findings demonstrated that although chronic exposure to heavy metal polluted sediments alters the functioning of both the nervous and endocrine systems, as well as plasticity of the gill epithelium, fish are able to trigger a series of physiological adjustments or adaptations interfering with specific neuroendocrine control mechanisms that enable their long-term survival.