Oral cancer is one of the most common malignant tumors of the head and neck, and it continues to represent a serious public health problem. Recent reports show the involvement of H19 long noncoding RNA (LncRNA) in oncogenesis but its mechanism associated with oral cancer remains unclear. Here, we identify an H19 transcript variant that lacks exon 4 in oral cancer specimens and carcinoma-derived cells. Depletion of H19 by short hairpin RNAs (shRNAs) targeting exon 1 but not exon 4 significantly inhibited oral cancer iCell-h120 cells growth and invasion in vitro and tumorigenesis of these cells in vivo. Through binding the ZEB1 mRNA, the variant H19 transcript without exon 4 promotes the expression of ZEB1 protein during epithelial–mesenchymal transition (EMT). Thus, these data reveal the role of a splicing events of H19LncRNA in oral tumorigenesis, and indicate that the splicing event of H19 can be served as potential therapeutic targets for oral cancer.