Abstract Cellular senescence is a hallmark of aging and the accumulation of senescent cells (SnCs) accelerates the aging process, contributing to aging‐related organ disorders. The PRDF1 and RIZ1 homology domain (PRDM) protein exhibits robust transcriptional regulatory activities and governs a wide range of biological processes. However, its roles in cellular senescence remain unclear. Here, this work demonstrates that PRDM16, a member of the PRDM protein family, decreases significantly in multiple organs of aged mice compared to young mice. Global Prdm16 deletion contributes to cellular senescence in various organs, including the kidneys, heart, lungs, hippocampus, stomach, and gut, leading to accelerated aging‐related organ injury. Furthermore, tubular‐specific Prdm16 deletion aggravates irradiation‐induced kidney aging and aging‐related kidney diseases in irradiated mice subjected to ischemia‐reperfusion surgery. Exogenous PRDM16 gene delivery by lentivirus effectively attenuates cellular senescence in vitro and in vivo. Mechanistically, PRDM16 improves glutathione metabolism and inhibits oxidative DNA damage, which is a driving force of senescence. Specifically, PRDM16 upregulates the transcription of glutathione S‐transferase mu 1 (GSTM1) by binding to its promoter region. Transfection with GSTM1 reverses PRDM16 deficiency‐induced cellular senescence and kidney aging. Collectively, these results provide a potential target for the investigation of anti‐aging therapies.