This study reports the design and optimization of proteolysis targeting chimeras (PROTACs) for the degradation of the METTL3–14 heterodimer complex, which is involved in RNA m6A modification and plays a key role in acute myeloid leukemia (AML) and other cancers. The design was based on the crystal structure of the METTL3–14 complex with a potent small-molecule inhibitor, UZH2. The initial PROTACs featured PEG- or alkyl-based linkers, with only the latter showing cell penetration. Subsequent optimization led to the synthesis of 26 PROTACs with different linker lengths and rigidity. Five PROTACs (14, 20, 22, 24, and 30) showed significant degradation of METTL3 and/or METTL14 in multiple AML cell lines and the prostate cancer cell line PC3, achieving degradation levels of up to 70%. These PROTACs also exhibited antiproliferative activity in PC3 cells but not in AML cell lines. The study highlights the importance of linker length and rigidity in achieving successful protein degradation and provides valuable insights into the design of effective PROTACs for targeted protein degradation.This study reports the design and optimization of proteolysis targeting chimeras (PROTACs) for the degradation of the METTL3–14 heterodimer complex, which is involved in RNA m6A modification and plays a key role in acute myeloid leukemia (AML) and other cancers. The design was based on the crystal structure of the METTL3–14 complex with a potent small-molecule inhibitor, UZH2. The initial PROTACs featured PEG- or alkyl-based linkers, with only the latter showing cell penetration. Subsequent optimization led to the synthesis of 26 PROTACs with different linker lengths and rigidity. Five PROTACs (14, 20, 22, 24, and 30) showed significant degradation of METTL3 and/or METTL14 in multiple AML cell lines and the prostate cancer cell line PC3, achieving degradation levels of up to 70%. These PROTACs also exhibited antiproliferative activity in PC3 cells but not in AML cell lines. The study highlights the importance of linker length and rigidity in achieving successful protein degradation and provides valuable insights into the design of effective PROTACs for targeted protein degradation.