The rearranged during transfection (RET) mutation such as the G810C mutation has significantly restricted the clinical application of selective RET inhibitors in the treatment of RET-driven cancers. This study designed and evaluated RET proteolysis targeting chimeras (PROTACs) based on selpercatinib (LOXO-292), identifying RD-23 as a potent and selective RET PROTAC. RD-23 effectively inhibited the proliferation of BaF3 cells with various RET mutations, showing IC50 values of 2.4 to 6.5 nM. It selectively induced degradation of the RETG810C mutation via the ubiquitin-proteasome system, with a DC50 (concentration causing 50% of protein degradation) value of 11.7 nM. Additionally, RD-23 exhibited oral bioavailability and superior antitumor effects compared to LOXO-292 in a Ba/F3-KIF5B-RETG810C xenograft mouse model. These results suggested that RD-23 is a promising candidate for treating RET-driven cancers.