<p>Oral squamous cell carcinoma (OSCC) is a prevalent malignancy characterized by local invasion, lymphatic metastasis, and poor prognosis. This study aimed to investigate the roles of interleukin-6 (IL-6) and matrix metalloproteinase-10 (MMP-10) in OSCC progression through clinical sample analysis, cellular experiments, and a subcutaneous xenograft model. IL-6 and MMP-10 levels were analyzed in 113 paired OSCC tissues and peritumoral clinically normal tissues using qRT-PCR, immunohistochemistry, and Western blot. Their associations with clinicopathological features and overall survival were also evaluated. Functional assays were conducted in SCC-25 and CAL-27 cells to assess the effects of IL-6 on proliferation, migration, and MMP-10 expression. JAK2/STAT3 pathway inhibitors and MMP-10 overexpression or knockdown were used to evaluate pathway involvement and the functional role of MMP-10. ChIP and luciferase assays examined STAT3 binding to the MMP-10 promoter. IL-6 and MMP-10 levels were elevated in OSCC tissues compared with adjacent non-cancerous tissues, with a positive correlation between IL-6 and MMP-10 expression. High expression of IL-6 or MMP-10 was associated with advanced clinicopathological features and shorter overall survival. The JAK2/STAT3 signaling pathway mediated IL-6-induced MMP-10 upregulation, as this effect was attenuated by pathway inhibition. STAT3 directly bound to the MMP-10 promoter and increased its transcriptional activity. MMP-10 knockdown reduced OSCC cell invasion and shifted EMT-related marker expression, whereas MMP-10 overexpression showed the opposite tendency. In vivo experiments demonstrated that IL-6 administration promoted tumor growth in nude mice, while IL-6 neutralization reduced tumor growth. These results support MMP-10 as a transcriptional target of STAT3 and suggest that the IL-6-JAK2/STAT3-MMP-10 axis contributes to OSCC progression.</p>