BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide. Early detection is critical for improving patient outcomes. This study investigated the potential of circulating tumour DNA (ctDNA) methylation markers, specifically Heart and Neural Crest Derivatives Expressed 2 (HAND2) and Glycoprotein M6A (GPM6A), as novel non-invasive biomarkers for CRC detection and treatment monitoring. METHODS: Plasma samples were collected from 40 CRC patients before and after treatment, as well as 40 healthy controls. Methylation levels of HAND2 and GPM6A in ctDNA were quantified using quantitative methylation-specific PCR (qMS-PCR). RESULTS: Methylation levels of HAND2 and GPM6A were significantly elevated in pre-treatment colorectal cancer (CRC) patients compared to post-treatment patients and healthy controls. Specifically, HAND2 methylation exhibited a statistically significant reduction following therapeutic intervention (pre-treatment: 55.75% ± 26.75 vs. post-treatment: 37.98% ± 22.93, p < 0.001), with no significant correlation observed between pre- and post-treatment levels (Pearson r = 0.1030, p = 0.53). Similarly, GPM6A methylation decreased markedly post-treatment (pre-treatment: 72.93% ± 18.06 vs. post-treatment: 49.48% ± 16.83, p < 0.001) yet demonstrated a statistically significant positive correlation between pre- and post-treatment values (Pearson r = 0.3181, p = 0.05). Receiver operating characteristic (ROC) curve analysis revealed robust diagnostic performance, with the combined HAND2 and GPM6A methylation model yielding an area under the curve (AUC) of 0.9213 (95% CI: 0.8569–0.9856, p < 0.001), surpassing the individual discriminative capacities of HAND2 (AUC = 0.8906) and GPM6A (AUC = 0.8881). Survival analysis leveraging the Cancer Genome Atlas (TCGA) dataset indicated a potential association between elevated methylation of both genes. It reduced survival probability, with a pronounced effect observed in rectal adenocarcinoma. CONCLUSION: HAND2 and GPM6A methylation in ctDNA are promising non-invasive biomarkers for CRC detection and monitoring, outperforming the diagnostic accuracy of traditional markers such as CEA or CA19-9. Further research is needed to validate these findings in larger cohorts and investigate their potential as markers for treatment response and disease recurrence. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12935-025-03898-5.