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DNA methylation, is catalyzed by DNA methyltransferases (DNMTs), and its aberrant patterns are implicated in thyroid cancer pathogenesis. The study aimed to investigate the association of DNMTs with thyroid cancer and evaluated the effects of sustained demethylating therapy in a cell-based study. DNMTs expressions in thyroid cancer were analyzed using GEO and TCGA datasets. Additionally, 16 paired and three unpaired papillary thyroid carcinoma (PTC) samples from Taipei Medical University (TMU), along with commercial tissue arrays, were analyzed. Furthermore, the effects of the covalent DNMT inhibitor, 5-azacytidine (5-Aza), and the DNMT1-selective inhibitor, GSK-3484862, on cell viability were evaluated in PTC and follicular thyroid carcinoma (FTC) cell lines. DNMT1 and DNMT3A were upregulated in PTC, with DNMT1 expression correlated with the BRAF mutation and lymph node invasion in TCGA data, findings further confirmed in the TMU cohort and tissue arrays. Short-term (24 h) 5-Aza treatment (1 and 5 µM) induced substantial cell death regardless of the DNA methylation status, whereas short-term GSK-3484862 (5 µM) treatment showed minimal cytotoxicity. In contrast, sustained low-dose GSK-3484862 treatment (approximately 1-3 weeks at 2 µM) effectively reduced global DNA methylation and decreased cell viability of TPC-1 and FTC-236 cells through apoptosis, rather than by inhibiting proliferation. In conclusion, DNMT1 overexpression in PTC suggests its involvement in thyroid carcinogenesis. Sustained inhibition of DNMT1 effectively reduced global DNA methylation and promoted apoptosis, highlighting the potential of prolonged DNMT1-targeted therapy. Further in vitro and in vivo studies are warranted to validate these results and elucidate the underlying mechanisms.