Understanding composition changes among tumor initiation and progression is critical to characterize the tumor microenvironment of oral cancer. Here, we profiled 205,000 single-cell transcriptomes and 58,800 single-cell epi-genomes of 25 oral cancer samples derived from three different sites: adjacent normal, pre-cancerous lesions, and tumor. The malignant epithelial cells exhibited distinct expression programs, and cells that enriched with cell-cycle program are prevalent in tumor samples and associated with worse survival.