To address the pharmacokinetic limitations of current selective estrogen receptor degraders (SERDs) and explore structurally novel ERα-targeted degraders, a series of coumarin derivatives were designed, synthesized, and biologically evaluated. Structure-activity relationship studies indicated that the phenoxy linker, 7- and 3-position bisphenolic hydroxyl groups, and R-configured basic side chain were critical for activity. Among them, compound 23g bearing an (R)-3-methylpyrrolidine moiety showed the most potent antiproliferative activity against MCF-7 cells, with an IC50 value of 0.015 μM. SPR analysis confirmed its high ERα affinity (K d = 3.4 nM). 23g induced concentration-dependent ERα degradation via the ubiquitin-proteasome pathway and showed limited cytotoxicity toward ERα-negative and normal mammary epithelial cells. Pharmacokinetic profiling in Sprague-Dawley rats demonstrated favorable oral bioavailability (27.45%) and a prolonged elimination half-life (11.82 h), supporting 23g as a promising coumarin-based SERD candidate.