The rearranged-during-transfection (RET) kinase is a validated target for the treatment of RET-altered cancers. Currently approved RET-selective kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), increase the oncogenic RET protein level upon treatment, which may affect their efficacy. We seek to reduce the oncogenic RET protein level and RET kinase activity simultaneously. Here, we report the development of proteolysis targeting chimera (PROTAC) degraders of oncogenic RET protein. Compound YW-N-7 exhibited dual action of selectively inhibiting and depleting RET protein both in vitro and in vivo. Proteomic analysis indicated that YW-N-7 is highly specific to RET. In cell cultures, reducing RET fusion protein potentiated the activity of LOXO-292. Furthermore, YW-N-7 showed significant activity in inhibiting KIF5B-RET-driven xenograft tumors in animals. This study exemplifies the feasibility of simultaneously inhibiting and degrading oncogenic RET kinase for cancer therapy.