Abstract Purpose: To investigate the regulation of epithelial-to-mesenchymal transition (EMT) in head and neck squamous cell carcinoma (HNSCC) and its importance in tumor invasion. Experimental Design: We use a three-dimensional invasive organotypic raft culture model of human foreskin keratinocytes expressing the E6/E7 genes of the human papilloma virus-16, coupled with bioinformatic and IHC analysis of patient samples to investigate the role played by EMT in invasion and identify effectors and upstream regulatory pathways. Results: We identify SNAI2 (Slug) as a critical effector of EMT-activated downstream of TP63 overexpression in HNSCC. Splice-form–specific depletion and rescue experiments further identify the ΔNp63γ isoform as both necessary and sufficient to activate the SRC signaling axis and SNAI2-mediated EMT and invasion. Moreover, elevated SRC levels are associated with poor outcome in patients with HNSCC in The Cancer Genome Atlas dataset. Importantly, the effects on EMT and invasions and SNAI2 expression can be reversed by genetic or pharmacologic inhibition of SRC. Conclusions: Overexpression of ΔNp63γ modulates cell invasion by inducing targetable SRC-Slug–evoked EMT in HNSCC, which can be reversed by inhibitors of the SRC signaling. Clin Cancer Res; 24(16); 3917–27. ©2018 AACR.