The expression and exact roles of miR-212-5p in CRC and the underlying molecular mechanism is still unclear. This study we aimed to investigate the expression and the role of miR-212-5p in colorectal cancer and further explore the underlying molecular mechanism. We first detected the expression level of miR-212-5p in colorectal cancer tissues and cells and we found that miR-212-5p was up-regulated in colorectal cancer. We performed TargetScan and Miranda databases to predict the putative targets of miR-212-5p, and the prediction was verified by dual-luciferase reporter assay. To investigate the role of miR-212-5p in colorectal cancer, a stable miR-212-5p-lowexpression cell line was established by using miR-212-5p inhibitor. MTT, cell migration and invasion assay were used to investigate the proliferation, cell migration and invasion ability of colorectal cancer HCT116 cells. Moreover, gene mRNA and protein expression were detected by qRT-PCR and western blotting. We found that miR-212-5p directly targets Smad4, and Smad4 was significantly increased after miR-212-5p down-regulation. After down-regulating miR-212-5p, the proliferation of HCT116 cells was significantly decreased, and the migration and invasion ability of HCT116 cells were markedly declined. In addition, the findings suggested that compared with the control, miR212- 5p low-expression significantly decreased the protein expression level of N-cadherin in HCT116 cells, while the E-cadherin expression level remarkably increased. In conclusion, microRNA-212-5p down-regulation suppresses colorectal cancer migration and invasion by up-regulating SMAD4.