Cadmium (Cd) is a toxic metal that threatens human health when enriched in crops.NRAMPs are a family of natural macrophage proteins reported to play a key role in Cd transport in plants. In order to explore the gene regulation mechanism of potato under Cd stress and the role ofNRAMPs family in it, this study analyzed the gene expression differences of two different Cd accumulation levels in potato after 7 days of 50 mg/kg Cd stress and screened out the key genes that may play a major role in the differential accumulation of Cd in different varieties. Additionally,StNRAMP2was selected for verification. Further verification showed that theStNRAMP2gene plays an important role in the accumulation of Cd in potato. Interestingly, silencingStNRAMP2increased Cd accumulation in tubers but significantly decreased Cd accumulation in other sites, suggesting a critical role ofStNRAMP2in Cd uptake and transport in potatoes. To further confirm this conclusion, we performed heterologous expression experiments in which overexpression ofStNRAMP2gene in tomato resulted in a threefold increase in Cd content, which further confirmed the important role ofStNRAMP2in the process of Cd accumulation compared with wild-type plants. In addition, we found that the addition of Cd to the soil increased the activity of the plant antioxidant enzyme system, and silencingStNRAMP2partially reversed this effect. This suggests that theStNRAMP2gene plays an important role in plant stress tolerance, and future studies could further explore the role of this gene in other environmental stresses. In conclusion, the results of this study improve the understanding of the mechanism of Cd accumulation in potato and provide experimental basis for remediation of Cd pollution.