Oral cancer, the most prevalent type of cancer in the head and neck region, has an overall five-year survival rate of less than 50%. Key risk factors for its development include tobacco use, alcohol consumption, betel nut chewing, and infections with human papillomavirus (e.g., HPV-16 and HPV-18). While various diagnostic technologies have been developed, some of which have progressed to regulatory-approved in vitro diagnostic systems, there has been no significant improvement in survival rates for patients with oral squamous cell carcinoma despite advancements in surgery, radiotherapy, and chemotherapy. This has prompted the exploration of gene therapy as a novel approach to treating oral cancer. Research indicates that genomic abnormalities and misregulations contribute to both spontaneous and hereditary malignancies. Gene therapy involves the introduction of genetic material into target cells, aiming to minimize harm to surrounding tissues. Various gene therapy techniques, including gene addition therapy, oncolytic virotherapy, suicide gene therapy, excision gene therapy, immunotherapy, and nucleic acid-based therapies, have been investigated both in vitro and in vivo. This review explores these innovative gene therapy strategies, highlighting their potential to address the limitations of conventional treatments and improve outcomes for oral cancer patients.