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<b>Background and Objective:</b> Oral Squamous Cell Carcinoma (OSCC), particularly tongue malignancies, remains a major global health concern due to late diagnosis and limited treatment options. <i>Salvadora persica</i> (Miswak), traditionally used by ancient Arabs for oral hygiene, contains numerous bioactive compounds with potential therapeutic value. This study aimed to evaluate the antioxidant properties of Miswak extract using different solvents, quantify its total phenolic and flavonoid content and assess its anticancer activity against an oral cancer cell line through <i>in vitro</i> and <i>in silico </i>approaches. <b>Materials and Methods:</b> Miswak extracts were prepared using water, acetone and ethanol to compare antioxidant capacity and phytochemical content. The extract exhibiting the highest activity was selected for further analysis. The ethanolic extract was subsequently tested on the human tongue carcinoma cell line (HNO97) using the Sulforhodamine B (SRB) assay to determine cytotoxicity. The ELISA was conducted to quantify TNF-α and VEGF-A levels, while real-time PCR was used to measure the expression of caspase-3 and caspase-7. Molecular docking was performed to evaluate the binding affinity of Miswak-derived compounds toward DAPK1, a key protein involved in regulating apoptosis. Statistical analyses were applied to assess the significance of the findings. <b>Results:</b> The ethanolic extract exhibited the highest antioxidant activity and was selected for anticancer evaluation. SRB assay results showed potent cytotoxicity against HNO97 cells with an IC<sub>50</sub> of 260.03 μg/mL. The ELISA confirmed significant downregulation of TNF-α and VEGF-A, indicating pronounced anti-inflammatory and anti-angiogenic effects. Real-time PCR demonstrated upregulation of caspase-3 and caspase-7, suggesting activation of apoptotic pathways. Molecular docking supported these observations by revealing strong binding affinities of the extract's bioactive compounds to DAPK1. <b>Conclusion:</b> The ethanolic extract of <i>Salvadora persica</i> demonstrates promising antioxidant, anti-inflammatory, anti-angiogenic and pro-apoptotic properties, indicating its potential as a natural therapeutic candidate for oral squamous cell carcinoma. These findings provide a strong foundation for further <i>in vivo</i> and preclinical studies to validate its efficacy and safety.