Inhibition of estrogen receptor alpha (ERα) signaling is an established therapeutic approach for the treatment of ER-positive (ER+) breast cancers, but new therapeutic strategies are urgently needed to overcome clinical resistance. In the present study, we describe the discovery and extensive evaluation of ERD-12310A as an exceptionally potent and orally efficacious PROTAC degrader of ERα. ERD-12310A achieved a DC50 value of 47 pM and is 10 times more potent than ARV-471. ERD-12310A displayed an improved pharmacokinetic profile in mice and rats over ARV-471. ERD-12310A attained tumor regression in the ER+, estrogen-dependent MCF-7 breast cancer xenograft model with wild-type ER and is more potent than ARV-471. Importantly, ERD-12310A achieved strong tumor growth inhibition in MCF-7 xenograft tumors harboring the clinically relevant ESR1Y537S mutation, which confers resistance to traditional antiestrogens. Our data position ERD-12310A as a promising candidate for further development as a potential therapy for ER+ breast cancer.