Acting as a nucleus-localized transcriptional activator, RsWRKY75 promotes ROS scavenging and Cd efflux by activating the transcription of RsAPX1 and RsPDR8 in radish. Radish (Raphanus sativus L.) is an important economical root vegetable crop worldwide. As a toxic heavy metal, cadmium (Cd) can dramatically hamper radish taproot quality as well as threaten human health. Although the WRKY transcription factors (TFs) play crucial roles in plant response to Cd stress, how WRKY TFs mediate Cd uptake and efflux remains elusive in radish. Herein, the RsWRKY75, belonging to the WRKY-IIc sub-group, displayed high expression in vascular cambium at the expanding stage, whose promoter activity and expression were obviously induced by Cd exposure at 24 h in radish root. RsWRKY75 was localized primarily to the nucleus and had transactivation activity in yeast and tobacco leaf cells. Transient transformation indicated that RsWRKY75 promoted Cd-induced ROS scavenging in radish cotyledons. Overexpression of RsWRKY75 led to increased root elongation but decreased Cd accumulation in Arabidopsis plants. Both in vitro and in vivo assays revealed that RsWRKY75 bound to the RsAPX1 promoter and activated its expression to eliminate excessive ROS accumulation. Moreover, RsWRKY75 activated RsPDR8 transcription by directly binding to its promoter, thereby promoting Cd efflux in the radish root. Collectively, we revealed a novel module of RsWRKY75-mediated ROS scavenging and Cd efflux in radish. These results would facilitate to establish genetic strategies to achieve RsWRKY75-dependent Cd extrusion and detoxification in radish.