Objective To investigate the effect of miR-377-5p on angiogenesis and lymphangiogenesis in colon cancer by downregulating vascular endothelial growth factor (VEGF)-C. Methods Subjects were divided into the miR- 377-5p interference, miR-377-5p negative control and miR -377-5p overexpression groups. Real-time fluorescence RT- PCR, Western blot, CCK-8, flow cytometry, cell scratches, Transwell assays, and angiogenesis experiments were used to detect miR-377-5p mRNA and protein expression, cell proliferation, apoptosis, migration, invasion, angiogenesis and lymphangiogenesis. Results miR-377-5p mRNA and protein expressions in the colon cancer tissue were significantly lower than those in the normal colon tissue ( both P< 0. 05). Compared with those of the miR-377-5p interference group, the mRNA and protein expressions in the miR-377-5p negative control and overexpression groups were significantly increased (both P< 0. 05). Compared with the miR-377-5p negative control group, miR-377-5p overexpression colon cancer cell proliferation in the miR-377-5p negative control and miR-377-5p overexpression groups was significantly reduced compared with that of the miR-377-5p interference group (P<0. 05). Colon cancer cell proliferation in the miR-377-5p overexpression group was significantly reduced compared with that of the miR-377-5p negative control group (P<0. 05). Colon cancer cell proliferation and apoptosis in the miR-377-5p negative control and overexpression groups were significantly increased compared with those of the miR-377-5p interference group (P<0. 05). The apoptotic ability of the colon cancer cells in the miR-377-5p overexpression group was significantly increased compared with that of the miR-377-5p negative control group (P<0.05 ). The wound-healing tests showed that the migration ability of colon cancer cells in the miR-377-5p overexpression group was significantly lower than that of the miR-377-5p interference and miR-377-5p negative control groups (P<0. 05). Colon cancer cells in the miR-377-5p overexpression group were also significantly less invasive than those of the miR-377-5p interference and negative control groups (P<0. 05). VEGF-A, VEGF-C, P-Akt, and VEGFR-3 protein levels were significantly lower in the miR-377-5p overexpression group than in the miR-377-5p interference and miR-377-5p negative control groups (P<0. 05). Microvessel density and lymphatic microvessel density were significantly lower in the miR-377-5p overexpression group than in the miR-377-5p interference and miR-377-5p negative control groups (P<0. 05). Conclusions Low miR-377-5p expression inhibited colon cancer cell proliferation, migration and invasion; promoted colon cancer cell apoptosis; and inhibited blood vessels and lymph in the tumor by directly targeting VEGF-C tube generation.