Fusion of the ETS (E-26 transformation-specific)-related gene (ERG) with transmembrane serine protease 2 (TMPRSS2) is a crucial step in the occurrence and progression of approximately 50% of prostate cancers. Despite significant progress in drug discovery, ERG inhibitors have yet to be approved for the clinical treatment of prostate cancer. In this study, we used computer-aided drug design (CADD)-based virtual screening to screen for potential inhibitors of ERG. In vivo and in vitro methods revealed that nifuroxazide inhibited the proliferation of a TMPRSS2:ERG fusion-positive prostate cancer cell line (VCaP) with an IC50 lower than that of ERG-negative prostate cancer cell lines (LNCaP, DU145 and WPMY cells). PARP1, the critical mediator of parthanatos, is known to bind ERG and required for ERG-mediated transcription. Nifuroxazide blocked this interaction, and overly activated PARP1, leading to cell death that was reduced by olaparib, a PARP1 inhibitor. These results show that nifuroxazide inhibits ERG, leading to parthanatic cell death.