DNA methyltransferase 1 (DNMT1), which catalyzes maintenance methylation of hemimethylated DNA during DNA replication, is overexpressed in cancer. Recently, the first-in-class DNMT1-selective noncovalent small-molecule inhibitors, GSK3484862 and GSK3685032, were discovered. These inhibitors were also reported to degrade DNMT1. However, structure-activity relationship (SAR) studies of these monovalent DNMT1 degraders are lacking. Here, we report our SAR studies of this scaffold on degrading DNMT1, which led to the discovery of multiple lead degraders, including compound (MS9024). Compound potently and selectively degraded DNMT1 in multiple cancer cell lines in a concentration-, time-, and proteasome-dependent manner without altering DNMT1 transcription. Further mechanism-of-action studies suggest that the DNMT1 degradation induced by was not mediated by lysosome or cullin RING E3 ligases but could potentially be mediated by HECT E3 ligases and/or UHRF1. Collectively, these studies pave the way for further developing DNMT1 monovalent degraders as potential therapeutics and useful chemical tools.