Objective The purpose of this study was to investigate the relationship between miR-152-3p and the KLF4/IFITM3 axis, thereby revealing the mechanism underlying colon cancer occurrence and development, consequently providing a promising target for colon cancer treatment. Methods Bioinformatics methods were implemented to analyze the differential expression of miRNAs and mRNAs in colon cancer, confirm the target miRNA, and predict the downstream targeted mRNAs. qRT-PCR and Western blot were performed to detect the expression of miR-152-3p, KLF4, and IFITM3. CCK-8 and colony formation assays were conducted for the assessment of cell proliferation, and flow cytometry was carried out for the detection of cell apoptosis. Finally, dual-luciferase reporter gene assay was employed to verify the targeting relationship between miR-152-3p and KLF4. Results miR-152-3p was highly expressed in colon cancer cells, whereas KLF4 was poorly expressed. Dual-luciferase assay verified that miR-152-3p targeted to bind to KLF4 and suppressed its expression. Moreover, silencing miR-152-3p or overexpressing KLF4 was found to downregulate IFITM3, thereby inhibiting cell proliferation and potentiating cell apoptosis. In rescue experiments, we found that miR-152-3p deficiency decreased the expression of IFITM3 and weakened cancer cell proliferation, and such effects were restored when miR-152-3p and KLF4 were silenced simultaneously. Conclusion In sum, we discovered that miR-152-3p can affect the pathogenesis of colon cancer via the KLF4/IFITM3 axis.