The maintenance of stocks of estuarine species strongly depends on the ability of the species to cope with environmental stress. In NW Spain, commercial clam beds, which are usually co-occupied by the seagrass Zostera noltei, are often exposed to reduced salinity caused by intense rainfalls. Our goals were to evaluate the effects of low salinity events on both juvenile clams and Z. noltei, including their interactions. A mesocosm experiment was performed to simulate three salinity decreases (35–35, 25–10, and 20–5), and several indicators of clam and seagrass performance were measured after 3 and 6 days of exposure and again after a recovery period of 4 days. No differences were observed in the non-native clam Ruditapes philippinarum, while oxygen consumption, clearance rate and growth decreased significantly in the native clams R. decussatus and Venerupis corrugata in response to low salinity stress. Zostera noltei indicators did not vary in response to low salinity exposure, except the sucrose content, which decreased. Moreover, the seagrass buffered juvenile clams from salinity fluctuations in the short term, although the interactions were weak. The species-specific sensitivity to low salinity should be a major concern in future management plans for the shellfish beds in the context of climate change.