Oral squamous cell carcinoma (OSCC) is known as one of the most malignant tumors with high recurrence and fatality rate. The poor tumor-targeting ability of traditional chemotherapeutic drugs has been a grand challenge for anti-OSCC therapy. Beyond that, a large quantity of tumor associated macrophages in OSCC tissues further diminish the anti-tumor effects of these drugs. Therefore, we produced a therapeutic nano drug delivery system (FA-PEG-PLA-JQ1) through encapsulating JQ1 [a small-molecule inhibitor of bromodomain containing protein 4 (BRD4)] into the folic acid (FA)-modified nanoparticle (PEG-PLA), which could prolong the half-life of JQ1 and target the tumor tissues. And then, JQ1 released from this nanoparticle could prevent OSCC growth inducing tumor cell apoptosis, inhibiting tumor angiogenesis and the polarization of M2 type macrophages. In conclusion, our date demonstrated the therapeutic benefits of FA-PEG-PLA-JQ1 against OSCC in vivo or in vitro, which could be a novel treatment strategy for OSCC in coming days.