Capo Peloro Lagoon is a coastal brackish system in northeastern Sicily (Italy), consisting of Ganzirri Lake and Faro Lake. The biological effects related to physicochemical parameters were assessed in two autochthonous clam species, Tapes decussatus and Tapes laeta, chosen for their abundance and economic interest, collected from the two Ganzirri Lake subbasins. Higher temperature and salinity values along with lower dissolved oxygen levels were recorded at the southernmost (site B) relatively to northernmost (site A) subbasin. A battery of biomarkers was investigated in clam gills, including histomorphological endpoint, cholinergic neurotransmission, oxidative stress, and hypoxia biomarkers. Both clam species from site B showed altered gill histomorphology attributable to inflammatory processes. A compromised cholinergic neurotransmission, stimulation of the antioxidant defense system, and onset of hypoxic adaptive responseswere also observed. Overall, data suggest that the environmental variables, as those recorded in the southernmost subbasin ofGanzirri Lake, adversely interfere with the physiological function of the gills, triggering a number of adaptive responses in the clams.