Cadmium (Cd) is a hazardous heavy metal that threatens human health through the consumption of contaminated rice. To mitigate Cd accumulation in rice grains, it is crucial to reduce Cd uptake. Nevertheless, the transcriptional mechanisms governing Cd uptake in rice remain largely unknown. This research identifies the transcription factor OsNAC5 in Oryza sativa as a positive regulator of the Cd transporter gene OsNRAMP1, thereby influencing Cd uptake. OsNAC5 is predominantly expressed in the roots, resides in the nucleus, and is upregulated by Cd-induced hydrogen peroxide (H2O2). Knocking out OsNAC5 results in lower Cd concentrations in both shoots and roots and heightens sensitivity to Cd. The expression of OsNRAMP1, enhanced by Cd stress, is dependent on OsNAC5. OsNAC5 binds to "CATGTG" motifs in the OsNRAMP1 promoter, activating its expression. The loss of OsNAC5 function leads to reduced Cd accumulation in rice grains. Our findings provide insights into the transcriptional regulation of Cd stress response in rice and propose biotechnological strategies to lower Cd uptake in crops.