Natural products have recently emerged as promising candidates for anticancer therapeutics. However, research on their use as adjuvants to existing chemotherapeutic agents in the treatment of oral squamous cell carcinoma (OSCC) remains limited. This study investigated the potential of METO, a methanol extract derived from Thuja orientalis, to induce apoptosis and its underlying mechanisms in the OSCC cell line HSC4. The results demonstrated that METO induces apoptosis in HSC4 cells, which is likely mediated through the activation of the ERK and JNK pathways, both of which were observed to be activated in METO-treated cells. Additionally, METO-induced apoptosis appears to involve signaling pathways associated with SOCS3 and p53. These findings highlight that METO exhibits strong anticancer activity in OSCC cells and suggest its potential as a promising chemotherapeutic agent for OSCC treatment.