PKMYT1 has recently emerged as a compelling therapeutic target for precision cancer therapy due to its synthetic lethality with oncogenic alterations such as CCNE1 amplification and mutations in FBXW7 and PPP2R1A. Current small molecule PKMYT1 inhibitors face limitations, such as insufficient molecular diversity and poor selectivity. We used our generative AI platform to develop a bifunctional PKMYT1 degrader by linking an entirely novel PKMYT1 inhibitor to an optimized cereblon (CRBN) binder. The lead PROTAC D16-M1P2 demonstrated dual mechanisms of PKMYT1 degradation and antagonism, with strong antiproliferative potency facilitated by high selectivity. It also exhibited favorable oral bioavailability, stronger pharmacodynamic effects relative to the PKMYT1 inhibitor alone, and robust antitumor response as a monotherapy in xenograft models. This first-in-class PROTAC serves as a precise chemical probe to explore PKMYT1 biology and a promising lead for further cancer therapy exploration.