INTRODUCTION: Colorectal cancer (CRC) is regarded as a serious global issue and is presently ranked second in the classification of gastrointestinal (GI) malignancies, with fast incidence and high mortality patterns. As the key "gene expression regulators", miRNAs critically contribute to tumor progression and development. For example, miR-21 (an oncomiR) and miR-143 (a tumor suppressor) are dysregulated through colorectal tumorigenesis. Accordingly, this study assesses the concomitant therapeutic impacts of "miR-21 suppression" (anti-miR-21) and "miR-143 restoration" (miR-143) on CRC cell proliferation and migration. METHODS: SW-480 cell lines (with overexpressed "miR-21" and downregulated "miR-143") were transfected via "anti-miR-21" and "miR-143" mimics, either independently or in combination. Next, cell viability assessment was performed through MTT assay. Then, apoptosis induction was examined with "Annexin V-FITC Kit", and via Propidium Iodide (PI) assay and DAPI staining. In the next step, "cell cycle condition" and "autophagy induction" were studied through flow cytometry. "Wound-healing assay" and "clonogenic assay" were employed to investigate the migration and proliferation of tumor cells. Ultimately, qRT-PCR was utilized to quantify the intensity of the effects of "anti-miR-21" and "miR-143" on gene expression profiles. RESULTS: Downregulation of "miR-21" expression and overexpression of "miR-143" were found to synergistically reduce the viability (while elevating apoptosis) of SW-480 cells by modulating CONCLUSION: Considering anti-cancer effects on cell growth, survival, and migration, it can be concluded that the concomitant suppression of "anti-miR-21" and "miR-143 restoration" might be introduced as a promising method for the therapy of CRC.