Estuarine intertidal zones are characterized by variable salinity regimes due to seasonal and daily fluctuations. Salt-marsh inhabitants, such as the mud fiddler crab Uca pugnax, are physiologically adapted to this habitat. Crustacean growth and development are energy demanding and sensitive hormonal processes which are susceptible to natural stressors. This study investigated physiological and metabolic changes in the molt cycle of U. pugnax in response to different salinity levels by assessing the survival, respiration, and post-molt tissue protein and carbohydrate content. Crabs were subjected to a limb regeneration and ecdysis challenge under four different salinity regimes. For the study, a limb was removed and its regenerative growth was photographed every two days. After ecdysis, crabs were dissected, and the tissues collected were analyzed for their protein and carbohydrate contents. Crabs held at 60 and 75 ppt seawater showed 100% mortality. Crabs at 60 ppt did not undergo basal limb growth. During limb regeneration, abnormal limb growth occurred solely in males. Post-molt 40 ppt crabs showed elevated respiration rates compared to 10 ppt crabs. Females and 25 ppt crabs had significantly more free carbohydrates in epithelial tissue than males and crabs at 10 and 40 ppt. As salinity decreased, epithelial protein content in females decreased while males experienced no change. Salinity did not affect the amount of acid, water or base-soluble exoskeleton protein. These physiological responses indicate that U. pugnax males and individuals exposed to extreme salinities are more likely to be impacted by salinity stress during limb regeneration and ecdysis.