This study is an integrated analysis of the transcriptome profile microRNA (miRNA) and its experimentally validated mRNA targets differentially expressed in the tumorigenic stem-like fraction of oral squamous cell carcinoma (OSCC). We had previously reported the coexistence of multiple drug-resistant tumorigenic fractions, termed side population (SP1, SP2, and MP2), and a nontumorigenic fraction, termed main population (MP1), in oral cancer. These fractions displayed a self-renewal, regenerative potential and expressed known stemness-related cell surface markers despite functional differences. Flow cytometrically sorted pure fractions of SP1 and MP1 cells were subjected to differential expression analysis of both mRNAs and miRNAs. A significant upregulation of genes associated with inflammation, cell survival, cell proliferation, drug transporters, and antiapoptotic pathways, in addition to enhanced transcriptome reprogramming mediated by DNA-histone binding proteins and pattern recognition receptor-mediated signaling, was found to play a crucial role in the transformation of the nontumorigenic MP1 fraction to the tumorigenic SP1 fraction. We also identified several differentially expressed miRNAs that specifically target genes distinctive of tumorigenic SP1 fraction. miRNA-mediated downregulation of stemness-associated markers CD44 and CD147 and upregulation of CD151 may also account for the emergence and persistence of multiple tumorigenic stem cell fractions with varying degrees of malignancy. The phenotypic switch of cancer cells to stem-like OSCC cells mediated by transcriptomal regulation is effectual in addressing biological tumor heterogeneity and subsequent therapeutic resistance leading to a minimal residual disease (MRD) condition in oral cancer. A detailed study of the interplay of miRNAs, mRNA, and the cellular phases involved in the gradual transition of nontumorigenic cancer cells to tumorigenic stem-like cells in solid tumors would enable detection and development of a treatment regimen that targets and successfully eliminates multiple, drug-resistant fractions of cancer cells.