Oral cancer ranks in the top 10 most prevalent malignancies worldwide. It is an aggressive tumor with frequent relapses and metastases and relatively modest survival rates that do not improve in spite of constantly evolving treatment modalities. Cancer stem cells are a subpopulation of tumor cells considered to be responsible not only for tumor initiation but also its aggressive behavior. Many efforts are directed at targeting those cells specifically. A class of small molecules, inhibitors of BET proteins (iBET), is emerging as a novel anticancer tool. Modulating the expression of microRNAs could also be a valid approach in cancer therapy. We aimed to study the effect of the iBET JQ1 combined with miR-21 silencing on oral cancer stem cells (CD44+ cells). CD44+ cells were sorted by flow cytometry and treated with JQ1 alone or in combination with miRNA-21 silencing. Following treatment, MTT, spheroid formation, invasion, and annexin V assays were performed, along with cell cycle and gene expression analyses. JQ1 in conjunction with miR-21 silencing showed considerable cytotoxicity led to a significant downregulation of cyclin D1, consistent with G1 cell cycle arrest, a significant caspase 3 upregulation in accordance with activation of apoptosis. The combined treatment approach also reduced CD44+ cell invasion capacity. Modulating chromatin structure with iBETs and silencing miRNA could be suitable epigenetic adjuncts to oral cancer treatment.