MicroRNAs (miRNAs) are important small molecules in cancer including oral squamous cell carcinoma (OSCC) which regulate gene expression at post-transcriptional levels. MiR-204-5p acts as a tumor suppressor in some of cancers, but the role of it in OSCC is not known. The aim of this study is to investigate the expression and functional roles of miR-204-5p in OSCC. The results showed that the expression of miR-204-5p was lower in cancer tissues or cells. Next, cell proliferation, cell cycle, migration and invasion were detected. It was found that miR-204-5p could enhance OSCC cell proliferation and metastasis. MiR-204-5p was predicted as a regulatory miRNA of CXCR4 in OSCC, and the data analysis indicated that there was a negatively relationship between miR-204-5p and CXCR4 expression in OSCC tissues from the patients. In a conclusion, our findings suggested that miR-204-5p may function as an inhibitory RNA molecule in OSCC by targeting CXCR4.