Purpose: Epigenetic changes can be detected in precancerous lesions, suggesting that may be involved in the early stages of carcinogenesis. The methylation of specifics genes has been correlated with the outcome of many different types of cancers. This study compared the levels of DNA methylation between normal and tumor tissues from patients with colorectal cancer (CRC). Methods: Candidate genes were screened using the Methyl-Profiler™ PCR Array System and the Dickkopf-related protein 2 (DKK2) genes were selected for study. DNA methylation of these genes was assessed by polymerase chain reaction–high-resolution melting (PCR–HRM) analysis. Results: Out of the 112 patients studied, 68 were controls with a mean age (SD) of 59.9 years (13.4) and 45 were patients with CRC with a mean age (SD) of 64.6 years (13.6). Among the patients with CRC, 25 were women, 28 were diagnosed with colon cancer and 18 were diagnosed with rectal cancer. The number of patients with Stage I, II, III, and IV of the disease, as per the TNM classification, were 2 (4.3%), 20 (43.4%), 18 (39.1%), and 2 (4.3%), respectively. Furthermore, the DKK2 gene had a higher methylation profile in the CRC tissues when compared to normal mucosa (p < 0.001), whereas the methylation profile analysis was not statistically significant when comparing the stages of the disease (p = 0.078). Conclusion: The presence of differentially methylated sequences of the DKK2 gene between the groups showed that the methylation changes of these genes could potentially be prognostic and predictive markers in CRC.