Cadmium (Cd) was a typical pollutant in Bohai. The ocean was a huge ionophore. Cd pollution broke the inherent ion balance of seawater, which might affect the ion homeostasis of organisms living in the ocean. Metal ions played vital role in organisms. Therefore, exploring the ion dysregulation caused by Cd was very necessary to understand the toxicity mechanism of Cd. In this study, the clams (Ruditapes philippinarum) were exposed to two environmental concentrations of Cd (5 and 50 μg L^-1) for 21 days. ICP-MS was used to evaluate changes in 16 ions. We found that higher concentration group caused obvious maladjustment of ion homeostasis. Correlation analysis found that Cd was significantly related to Zn, Sr, Mo and Se. With Cd concentration reached the toxicity threshold, ion homeostasis was completely destroyed. These caused energy stress, damaged genetic material and induced death-related pathways. Integrating the results of the transcriptome and metabolome, we found that Ca²⁺, Mg²⁺, Fe²⁺ and Mn²⁺ were disturbed by Cd²⁺, which had adverse effect on apoptosis and glycolysis. The stress-related genes were significantly up-regulated in the lower Cd-treated group. However, apoptosis-related genes were significantly upregulated in the higher Cd-treated group. In addition, we discovered that Se was a crucial element, which protected the clams from Cd stress in numerous ways. This work provided a new method and perspective for toxicity mechanism and response caused by Cd in organisms living in sea water.