BACKGROUND/AIM: Oral squamous cell carcinoma (OSCC) has limited treatment options. This study investigated imipramine, a tricyclic antidepressant, as a potential therapy for OSCC using a SAS-bearing xenograft animal model. MATERIALS AND METHODS: The SAS-bearing xenograft model evaluated imipramine's impact on tumor growth. The control group received no treatment, while the imipramine-treated group received regular doses. Tumor growth, confirmed by imaging, and histological analysis assessed size and weight. Imipramine's effects on apoptosis, epithelial-to-mesenchymal transition (EMT), and transcription factors (AKT, ERK, STAT3) were analyzed. RESULTS: Imipramine significantly suppressed tumor growth within 6 days of treatment, with sustained activity. Computer tomography (CT) scans and histology confirmed reduced size and weight by imipramine. Imipramine induced apoptosis via caspase-dependent/-independent pathways, inhibited EMT, and down-regulated phosphorylated AKT, ERK, and STAT3. CONCLUSION: Imipramine shows promise as an effective OSCC therapy, inhibiting tumor growth, inducing apoptosis, and inhibiting EMT. Its impact on transcription factors and modulation of the AKT/ERK/STAT3 pathway suggest a multifaceted approach.