Squamous cell carcinoma is one of the most common malignancies in head and neck region. Primary tumors, especially derived from undifferentiated cells, tend to have an aggressive phenotype, mainly characterized by local recurrence and distant metastasis. In this study we found that Id-1, a negative regulator of tissue specific transcription factors, is highly expressed in head and neck squamous carcinoma cells (HNSCC), and that the expression correlated with the malignant phenotype, i.e., cell proliferation and invasion. Id-1 knockdown dramatically reduces squamous cell invasion that is accompanied by profound morphologic changes and robust reduction in expression levels of mesenchymal markers. In addition, reduction in tumor growth and neoangiogenesis were observed in vivo, indicating knock-down of Id-1 drastically suppresses VEGFA expression. Our results also showed that VEGFA-autocrine loop regulated by Id-1 phosphorylates tylosine kinase pathways including Srk and FAK, and therefore manifests invasive phenotypes. Furthermore, we demonstrated that a non toxic compound, cannabidiol, significantly downregulates Id-1 gene expression and associated squamous cell proliferation and invasiveness. Taken together, these results suggest that Id-1 controls cancer cell phenotype in culture and in vivo, and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of patients with HNSCC.