WYL domain containing transcription factors play critical roles in regulating fundamental processes in bacterial physiology. The Caulobacter crescentus DriD protein is a WYL transcription regulator recently shown to activate a DNA damage response pathway that is independent of the major bacterial SOS repair system. DriD is a 327-residue homodimer and contains a unique fold composed of a N-terminal winged helix-turn-helix DNA binding domain (DNABD), linker region, three-helix bundle (3HB), WYL domain, and WYL C-terminal extension (WCX) dimerization domain. DriD binds ssDNA, which acts as a genotoxic signal that accumulates during double stranded DNA breaks, within its WYL domain. This interaction activates target DNA binding by DriD. However, the molecular mechanism by which ssDNA binding to the WYL domain, which is ~50 Å from the DNABD, activates DriD is unknown. Here, we describe structural and biochemical studies that indicate a novel allosteric mechanism of DriD activation. These data indicate that there is an inhibitory interaction formed between the DNABD and 3HB in the apo form, which is freed upon ssDNA binding. DriD represents the largest class of WYL regulator and thus can serve as a model for understanding activation by WYL activators including those in pathogenic bacteria.