Emerging evidence suggests that dysregulation of miR-153-3p may contribute to tumor development and progression in several types of human cancers. However, its role inoral squamous cell carcinoma (OSCC) is still unknown. MicroRNA profiles were obtained via miRNA microarray in OSCC tissues and adjacent normal tissues, and quantitative RT-PCR was performed to further validate microarray data. Subsequently, associations of miR-153-3p with Nrf2 were assessed using Pearson correlation. The clinical significance of miR-153-3p in OSCC was analyzed using receiver operating characteristic (ROC) curve. In vitro, wound healing and Transwell assays, as well as western blot were conducted to determine the biological function of miR-153-3p in CAL-27 cells transfected with miRNA mimics, inhibitor, or the empty vector. The miR-153-3p target was validated through a luciferase reporter assay, RT-PCR, and western blot. miRNA microarray revealed 18 aberrant miRNAs in OSCC tissues, including miR-153-3p, which was significantly reduced (P < 0.01); miR-153-3p expression was lower in patients with aggressive tumors (P < 0.01). Additionally, Nrf2 mRNA amounts, which were higher (P < 0.01) in OSCC tissues, showed a negative correlation with miR153-3p levels (r = -0.74, P < 0.001). Moreover, miR-153-3p inhibited cell migration and invasion abilities in vitro (P < 0.01) and Nrf2 was confirmed as a target of miR-153-3p. MiR-153-3p is downregulated in human OSCC tissues, and is associated with tumorigenesis of oral squamous cells; in agreement, miR-153-3p inhibits CAL-27 cell migration and invasion by downregulating Nrf2.