The relentless pursuit of innovative hydrophobic tags remains a formidable challenge within the realm of targeted protein degradation. Herein, we have uncovered the remarkable potential of D-ring-contracted artemisinin as a potent hydrophobic tag that demonstrates exceptional degradation efficiency. We have crafted a series of conjugates by fusing D-ring-contracted artemisinin with raloxifene, and among these, RA3 has emerged as a promising candidate for degrading estrogen receptor α (ERα). In a breast cancer xenograft mouse model, RA3 induced pronounced tumor growth inhibition, surpassing the performance of the FDA-approved ERα degrader, Faslodex. Furthermore, the versatility of D-ring-contracted artemisinin as a hydrophobic tag has been confirmed in its ability to enhance the degradation of cyclin-dependent kinase 6 (CDK6) and histone deacetylases (HDACs). Our work not only underscores the therapeutic potential of artemisinin derivatives in targeted protein degradation but also paves new avenues for advancing the field of protein-based drug design.