The mechanism of endocrine resistance in breast cancer (BC) extends beyond ESR1 mutations to include compensatory androgen receptor (AR) signaling. However, current therapeutic agents directed at the AR ligand-binding pocket (LBP) face the risk of failure due to mutations within this pocket. Herein, we reported a series of PROTACs targeting the AR coactivator binding site (AR-CBS) to overcome endocrine resistance in AR+ BC. Among which, degrader 18o could not only effectively degrade AR, but also potently inhibit the proliferation of MCF-7 and multiple mutant or resistant BC cells. Simultaneously, 18o effectively blocked estrogen receptor α (ERα) signaling through a dual mechanism involving ERα protein downregulation and suppression of its transcriptional activity. Importantly, 18o exhibited excellent antitumor activity in both MCF-7 and LCC2 xenografted models. This proof-of-concept study confirms that AR-CBS is a promising target for BC treatment and highlights degrader 18o as a potential candidate for overcoming the endocrine resistance.