Cancer cells metastasize by entering the lymphatic system. Regional lymph-node dissemination is the first detectable step in the metastasis of oral squamous cell carcinoma (SCC) and is highly correlated to the prognosis of the disease. Cold shock domain protein A (CSDA) is a DNA-binding protein that represses angiogenesis and lymphangiogenesis by directly binding to hypoxia response element (HRE) and serum response element (SRE). In our study we used the cell line NR-S1M, a mouse SCC model with a high rate of lymph-node metastasis. Into these cells we transfected the expression-plasmid coding for full-length mouse CSDA. Of importance, we showed that overexpression of CSDA significantly inhibits the production of VEGF-A and VEGF-C in NR-S1M cells. The overexpression of CSDA in NR-S1M cells inhibited tumor growth, inhibited regional lymph-node metastasis, and reduced the density of blood vessels and lymphatic vessels in the primary tumors in vivo. Our results support the hypothesis that VEGF-A and VEGF-C are crucial regulators of angiogenesis and lymphangiogenesis in NR-S1M cells. Therefore, they are promising targets for CSDA overexpression gene therapy to inhibit tumor growth and lymph-node metastasis in SCC.