<p>Oral squamous cell carcinoma (OSCC), the most prevalent oral cancer, often exhibits local bone invasion. Interferon-induced protein with tetratricopeptide repeats 2 (IFIT2) has been identified as a tumor suppressor in OSCC, though its role in bone invasion remains unclear. This study aimed to investigate the involvement of IL-6 as a driver of bone invasion in OSCC with depleted IFIT2 expression and to evaluate the clinical relevance of IFIT2 and IL-6. IFIT2 knockdown significantly increased IL-6 mRNA and secretion levels in OSCC cells, indicating IFIT2’s potential regulatory role in inflammation within the tumor microenvironment. Elevated IL-6 levels in IFIT2-depleted OSCC cells markedly enhanced osteoclast differentiation and bone resorption. Neutralizing IL-6 reversed these effects, confirming IL-6 as a key mediator of bone invasion in OSCC cells. These results indicate that IL-6 as driver of bone invasion in IFIT2-depleted OSCC cells. Clinically, serum IL-6 concentrations were significantly higher in patients with advanced-stage tumors (T4) compared to early stages (T1–3; <i>p</i> = 0.027), supporting IL-6’s role as a progression marker. Stage IV OSCC patients exhibited higher IL-6 levels compared to stages I–III, further substantiating IL-6’s prognostic significance in advanced OSCC (<i>p</i> = 0.043). Serum IL-6 positively correlated with pro-tumorigenic cytokines, including VEGF-α and G-CSF. Notably, a high IL-6/IFIT2 ratio was associated with reduced median survival among OSCC patients. These findings indicate that IFIT2 depletion enhances OSCC-induced bone invasion predominantly through IL-6-mediated osteoclast activation, establishing the IL-6/IFIT2 axis as a critical regulator of OSCC progression and metastasis.</p>