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The Notch signaling pathway is frequently altered in Oral Squamous Cell Carcinoma (OSCC), the most common malignant neoplasm of the oral mucosa. In this study, we aimed to elucidate the functional role of this pathway in OSCC initiation and progression. Using transgenic animal models, advanced imaging, and next-generation-sequencing techniques, we analyzed Notch-dependent changes driving OSCC. We found specific expression patterns of Notch1 and Delta-like-4 confined to the malignant tissue, while Jagged1 was downregulated in OSCC. This mutually exclusive expression of Delta-like-4 and Jagged1 occurs at the early hyperplastic stage and persists until more advanced stages of the tumor. Transcriptomic analyses confirmed the dysregulation of the Notch pathway circuitry associated with a genetic signature for undifferentiation in OSCC. Furthermore, pharmacological Notch inhibition significantly impaired cancer cell motility. Taken together, these results reveal the pivotal importance of the Notch1/Delta-like-4 signaling axis as a central oncogenic driver in OSCC.