Prostate cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male cancer mortality in the western countries. The second-generation antiandrogen enzalutamide (ENZa) can prolong survival time for patients with mCRPC. However, the overexpression of glucocorticoids receptor (GR) in mCRPC cells causes the resistance of antiandrogen and leads to the failure of androgen receptor (AR) targeting therapy. Herein, based on the chemical structures of antiandrogen and crystal structure of GR, we set up to develop GR/AR (GR and AR) dual antagonist by virtual screening and biological evaluation. We identified Z19 as a dual AR/GR antagonist. Z19 inhibited the transcription activity of both AR and GR, reducing both protein and mRNA level of the downstream proteins of GR and AR signaling, and provided a potential lead compound for the development of novel treatment agents of prostate cancer. Our work demonstrates that rational drug design is an efficient strategy in development of the GR/AR dual antagonist for the treatment of prostate cancer.