Paternally expressed gene-10 (PEG10) could participate in several carcinomas and might be regulated by miR-491. To now, miR-491 was found to play an important role in the sensitivity and mechanism of drug usage in the treatment of colorectal cancer, and drug resistance is a key factor to affect the disease healing. In this study, miR-491, PEG10, Wnt1, and β-catenin expression levels and their correlation with colorectal cancer were assessed in cancer tissues and adjacent parts. And the target relationship between PEG10 and miR-491 was verified. Meanwhile, the impaction of Curcumin on miR-491, PEG10, and Wnt/β-catenin signaling pathway were analyzed in HCT-116 cells. The effects of PEG10 and Curcumin on human HCT-116 cells proliferation and apoptosis were investigated by MTT and flow cytometry assay. Results showed that the expression of miR-491 in colon cancer tissues was decreased, but PEG10, Wnt1, and β-catenin were higher than that in adjacent tissues. The PEG10 gene 3' UTR could combine with miR-491 seed sequence and miR-491 overexpression could cause a decrease in PEG10, Wnt1, and β-catenin levels in human HCT-116 cells. Furthermore, PEG10 overexpression increased the expression levels of Wnt1 and β-catenin, thereby promoting cell proliferation and inhibiting apoptosis. In addition, Curcumin could up-regulate miR-491, inhibit PEG10, and Wnt/β-catenin signaling pathway. Consequently, Curcumin reduced HCT-116 cells proliferation and promoted cells apoptosis via the miR-491/PEG10 pathway. In conclusion, PEG10 was a target gene of miR-491, miR-491/PEG10 strengthen the sensitivity of Curcumin in HCT-116 cells proliferation and apoptosis, which might act as an ideal diagnostic biomarker treatment methods.