The receptor tyrosine kinase, recepteur d'origine nantais (RON), is known to be associated with the progression, metastasis, and prognosis of various types of cancers. Nevertheless, the role of RON in human oral squamous cell carcinoma (OSCC) is unclear. This study evaluated whether RON affects oncogenic behavior, oncogenic signaling pathways, and clinical outcomes, including survival, in human OSCC. Reverse transcription‑PCR, quantitative PCR, western blotting and immunohistochemical staining were used to determine mRNA and protein expression levels of RON. Cell invasion, migration and apoptosis assays were used to assess the functional effects of small interfering RNA‑mediated knockdown of RON or snail family transcriptional repressor 2 (SLUG). RON knockdown suppressed tumor cell invasion and migration and enhanced apoptosis in human OSCC cells. RON knockdown also decreased the phosphorylation of MAPK signaling proteins, such as ERK1/2, JNK and p38. In addition, RON knockdown suppressed the expression of the epithelial mesenchymal transition (EMT)‑related transcription factor, SLUG. SLUG knockdown blocked the enhancement of cell invasion and migration induced by macrophage‑stimulation protein (MSP)‑mediated RON activation in OSCC cells. The cell morphology was changed to spindle‑like shape under MSP‑mediated RON activation in OSCC cells. RON was overexpressed in both fresh and paraffin‑embedded human OSCC tissues. Taken together, these results indicate that RON contributed to tumor progression by regulating the EMT‑related factor, SLUG, and the MAPK pathway in OSCC. This study may provide a theoretical basis for the application of RON‑targeting agents, currently being studied in various cancer fields, for the treatment of OSCC.