Salinity can affect the physiological and productive characteristics of bivalves. The razor clam Sinonovacula constricta naturally distributing in intertidal zones and estuarine waters is extensively cultured in China. High-salinity is a serious threat to its culture, especially in pond culture model. Here, we investigated the effects of high-salinity on the survival, gill tissue, enzyme activity and free amino acid content of S. constricta. Individuals were randomly divided into six groups treated with different salinities of 20, 25, 30, 35, 40, and 45 ppt. The median lethal salinity calculated by linear regression and probit analysis methods were similar, with 46.61, 43.17, 36.99, 35.99, and 34.99 ppt by linear regression, while 44.63, 42.87, 38.45, 37.32, and 36.17 ppt by probit analysis at 72, 96, 120, 144, and 168 h, respectively. Furthermore, paraffin section revealed that the gill of razor clam shrunk quickly under high-salinity and dissolved at 48 h under salinity of 40 ppt, but not under 30 ppt. In addition, the activities of three enzymes including Na+-K+-ATPase, acid phosphatase and alkaline phosphatase changed significantly under high-salinity. Besides, the contents of total free amino acids (TFAAs) in the gill tissues were 61.25 ± 1.58, 89.36 ± 4.18, and 111.98 ± 1.46 mg⋅g–1 at salinity of 20, 30, and 40 ppt, respectively, indicating increasing TFAA contents with salinity. Notably, several amino acid species including taurine, alanine, proline, glycine and glutamic showed significantly changed contents in response to salinity variation, suggesting these amino acids might play an important role in razor clam’s adaptation to salinity stress. Combining all these results, it was referred that razor clams may adapt to moderately high-salinity of 30 ppt in a short time through osmotic adjustment. Although a small proportion of individuals could survive under the salinity of 35 ppt, the death of most individuals still suggested it can hardly be accepted in aquacultural production. Notably, living under a salinity of 40 ppt for more than 48 h could cause great damage to razor clams. Therefore, the seawater salinity is recommended to be lower than 30 ppt for S. constricta aquaculture. Overall, this study provides guidance for the culture and breeding of high-salinity tolerant razor clams.