The present study was performed to evaluate the effects of calcium (Ca) pre-exposure and then waterborne cadmium (Cd) exposure on metal element accumulation, enzymatic activities, histology, and ultrastructure in Synechogobius hasta and test the hypothesis that Ca could protect against Cd-induced toxicity in the fish species. Three hundred sixty fish [initial mean weight 25.5 ± 0.1 g (mean ± SEM)] were stocked in 18 circular fiberglass tanks (water volume: 300 l), 9 of which were pre-exposed to Ca at a rate of 400 mg Ca/l for 9 days and then exposed to concentrations of 0, 79.3, and 158.6 μg Cd/l for 9 days. Another 9 tanks were cultured in natural seawater (no extra Ca addition) for 9 days and then exposed to concentrations of 0, 79.3, and 158.6 μg Cd/l for 9 days. Both Ca pre-exposure and then waterborne Cd exposure influenced the accumulation of metal elements [cadmium (Cd), copper, zinc, and iron] in several tissues (muscle, gill, liver, spleen, and intestine), changed hepatic intermediary metabolism, and induced histological and ultrastructural alterations in tissues. In general, Ca pre-exposure seemed to mitigate the severity of Cd-induced mortality and histopathological injuries indicating that Ca pre-exposure had the capacity to decrease Cd toxicity in S. hasta.