Histone deacetylases (HDACs) can regulate the progression of various cancers, while their roles in oral cancer cells are not well known. Our present study found that the HDAC1 was over expressed in oral squamous cell carcinoma (OSCC) cells and tissues. Targeted inhibition of HDAC1 via its specific inhibitor PCI24781 or siRNA can inhibit the proliferation ofOSCC cells and increase their sensitivity to the chemosensitivity such as doxorubicin treatment. HDAC1 can regulate the expression of proliferating cell nuclear antigen (PCNA) via decreasing its mRNA stability. While over expression of PCNA can attenuate HDAC1 inhibition induced suppression of cell proliferation. We checked the expression of various miRNAs which can target the 3'UTR of PCNA. Results showed that HDAC1 can negative regulate the expression of miR-154-5p, inhibitor of miR-154-5p can attenuate PCI24781 treatment decreased PCNA expression and cell proliferation. Collectively, our present study suggested that HDAC1 can promote the growth and progression of OSCC via regulation of miR-154-5p/PCNA signals.