Protein N-terminal methylation catalyzed by N-terminal methyltransferase 1 (NTMT1) is an emerging methylation present in eukaryotes, playing important regulatory roles in various biological and cellular processes. Although dysregulation of NTMT1 has been linked to many diseases such as colorectal cancer, their molecular and cellular mechanisms remain elusive due to inaccessibility to an effective cellular probe. Here we report the design, synthesis, and characterization of the first-in-class NTMT1 degraders based on proteolysis-targeting chimera (PROTAC) strategy. Through a brief structure-activity relationship (SAR) study of linker length, a cell permeable degrader 1 involving a von Hippel-Lindau (VHL) E3 ligase ligand was developed and demonstrated to reduce NTMT1 protein levels effectively and selectively in time- and dose-dependent manners in colorectal carcinoma cell lines HCT116 and HT29. Degrader 1 displayed DC₅₀ = 7.53 μM and D_max > 90% in HCT116 (cellular IC₅₀ > 100 μM for its parent inhibitor DC541). While degrader 1 had marginal cytotoxicity, it displayed anti-proliferative activity in 2D and 3D culture environment, resulting from cell cycle arrested at G0/G1 phase in HCT116. Label-free global proteomic analysis revealed that degrader 1 induced overexpression of calreticulin (CALR), an immunogenic cell death (ICD) signal protein that is known to elicit antitumor immune response and clinically linked to a high survival rate of patients with colorectal cancer upon its upregulation. Collectively, degrader 1 offers the first selective cellular probe for NTMT1 exploration and a new drug discovery modality for NTMT1-related oncology and diseases.