Transcription factors play a key role in the development of diverse cancers, and therapeutically targeting them has remained a challenge. In prostate cancer, the gene encoding the transcription factor ERG is recurrently rearranged and plays a critical role in prostate oncogenesis. Here, we identified a series of peptides that interact specifically with the DNA binding domain of ERG. ERG inhibitory peptides (EIPs) and derived peptidomimetics bound ERG with high affinity and specificity, leading to proteolytic degradation of the ERG protein. The EIPs attenuated ERG-mediated transcription, chromatin recruitment, protein-protein interactions, cell invasion and proliferation, and tumor growth. Thus, peptidomimetic targeting of transcription factor fusion products may provide a promising therapeutic strategy for prostate cancer as well as other malignancies. •ERG inhibitory peptides (EIPs) interact specifically with the DNA binding domain of ERG•EIPs block ERG-mediated transcription and recruitment to target gene loci•Binding of EIPs leads to proteolytic degradation of ERG protein•Retroinverso EIPs suppress tumor growth, intravasation, and metastasis in vivo Wang et al. identify peptides that interact with the DNA binding domain of ERG, thereby attenuating protein-protein interactions and chromatin recruitment of ERG and inducing ERG degradation. These peptides reduce proliferation, invasion, and tumor growth of prostate cancer cells with the TMPRSS2:ERG gene fusion.