Oral squamous cell carcinoma (OSCC) is one of the most common tumors worldwide and has one of the highest mortalities. The progression of OSCC is accompanied by changes in the levels of many genes. Iroquois homeobox 5 (IRX5), a novel protein involved in several embryonic developmental processes, has been found in recent years to play a significant role in regulating the growth of malignant tumors. However, its role and mechanism in OSCC are still unclear. In this study, we used nano-PCR to examine the levels of IRX5 in OSCC tissues. Through overexpression and knockdown experiments, we researched the role of IRX5 in regulating OSCC cell multiplication, metastasis, and epithelial-mesenchymal transition (EMT). The results demonstrated that IRX5 expression is higher in OSCC tissues in contrast to adjacent tissues. Overexpression of IRX5 promotes the multiplication, metastasis, invasion, and EMT of OSCC cells. Additional bioinformatics analysis showed that miRNA-147 can target the 3'UTR end of IRX5 and negatively regulate its expression, and overexpression of miRNA-147 can weaken the cancer-promoting effect of IRX5. In conclusion, this study found that IRX5 plays a role in promoting cancer in OSCC, and IRX5 is also negatively regulated by miRNA-147.