SIMILAR TO RCD-ONE (SRO) family members and transcription factors (TFs) often improve plant antioxidant capacity through interaction and co-regulation and participate in plant resistance to drought and high-salt stress. However, whether SROs are involved in the response to heavy metal stress, especially SRO genes with a specific response and tolerance characteristics to cadmium (Cd) stress, remains unclear. We first identified six SRO genes in the potato genome by PARP and RST domains. Special and conserved StSROs were found, and the spatio temporal tissue-specific expression patterns and co-expression network diagrams of StSROs under the stress of 5 heavy metals were constructed. Second, we identified StSRO6 as a major effector gene (StSRO6-MEG) and StSRO5 as a secondary effector gene (StSRO5-SEG) through a comprehensive analysis. Interestingly, they may hold true for various physiological or stress responses in plants. In addition, using systematic genomics and comparative omics techniques, the key gene StSRO6 that affects the difference in Cd accumulation was discovered, cloned in the low-Cd accumulation “Yunshu 505”, and transformed into the yeast mutant ycf1 for overexpression. The results proved that StSRO6 could confer Cd tolerance. Finally, through transient expression and in vitro culture tests, we hypothesized that StSROs 5/6 are regulated by the transcription factor StWRKY6 and mediates the reactive oxygen species (ROS) system to confer Cd tolerance. These findings offer a new perspective for understanding the mechanisms underlying Cd tolerance in plants, and simultaneously provide clues for the development of biological agents for preventing and controlling Cd migration and transformation.