Apoptosis is an important process of cell death that controls the intrinsic and extrinsic pathways. Syringic acid (SRA)-a phenolic compound well-known in traditional Indian Ayurvedic medicine-has been reported to suppress cell proliferation of various cancer cells. Therefore, the current study aimed to investigate the inhibitory role of SRA on the proliferation of oral squamous cell carcinoma cells (SCC131) via reactive oxygen species (ROS) and induced mitochondria-mediated apoptosis. The study results showed that SRA (IC 50) was able to induce apoptosis in SCC131 cells via increased ROS generation, alteration of mitochondrial membrane potential, nuclear fragmentation, apoptotic morphological differences, and DNA injury. Moreover, SRA inhibited proliferative markers such as proliferating cell nuclear antigen and cyclin D1 protein expression in SCC131 cells. A diminished level of B-cell lymphoma 2 (Bcl-2) and augmented level of Bcl-2-associated X protein (Bax) were considered as markers of apoptotic cell death. In addition, SRA was able to decrease Bcl-2 and increase mutant p53, caspase-9, Bax, and caspase-3 expression in SCC131 cells. Taken together, SRA succeeded in inhibiting SCC131 cell growth through the ROS and mitochondria-mediated apoptosis in oral cancer cells. K E Y W O R D S apoptosis, mitochondrial membrane potential, oral squamous cell carcinoma, reactive oxygen species, syringic acid 1 | INTRODUCTION Oral squamous cell carcinomas (OSCCs) are malignancies that develop in the mouth, including the gums, tongue, skin lining, and/or the lips. Recently, tumor proliferation statistics reported 263 900 new cases and 128 000 deaths from oral cancer worldwide. [1] Although there are various inexpensive and effective saleable drugs in the market that can partially cure cancer, they are often associated with severe side effects mainly due to the continuous intake of the drug. [2] Nowadays, radiotherapy, chemotherapy, and surgery have become the most widely used techniques for cancer management. However, some challenges are still found in preventing toxicity and ensuring the effectiveness of chemotherapeutic drugs or radiotherapy in tumor cell therapy. [3] Recently, natural dietary agents similar to vegetables and fruits have become greatly accepted at the level of research and in practice for their capability to repress cancer and diminish the danger of cancer cell proliferation. [4] Chemoprevention using nontoxic agents might be a better approach for decreasing the occurrence of cancers. [5] Developing novel phytochemicals which are cost-effective, nontoxic, and have physiological bioavailability represents another promising approach that could be targeted by organizations facing cancer. [6] Apoptosis is programmed cell death that is implicated in many human cancers. The characteristic morphological alterations observed include mitochondrial depolarization, cellular destruction, cell reduction, extensive plasma membrane, and separation of cell fragments