Oral cancer has high mortality and recurrence rates. This is attributed to resistance to the process of regulated cell death and resistance to radiotherapy and chemotherapy. Oral squamous cell carcinoma (OSCC) accounts for the majority of oral cancers. Its prognosis varies with the site, clinical stage, and histological grade of the tumor. Owing to the variation in the biological behavior of OSCC, the existing prognostic parameters have some limitations in terms of providing precise information on prognosis. The remarkable biological effects of vitamin D against oral cancer have been documented in various studies. These include antiproliferative and anti-invasive effects, inhibition of angiogenesis, stimulation of mutual adherence of cells, and induction of apoptosis in OSCC. Furthermore, vitamin D increases the sensitivity of OSCC tumor cells to chemotherapy. This phenomenon has been observed in tumors that are resistant to chemotherapy. These findings indicate that the biological effects of vitamin D may provide significant prognostic value in oral cancer patients. In addition, the administration of vitamin D improves the quality of life of patients with inoperable oral cancer lesions in addition to the reported increase in tumor sensitivity to chemotherapy. A low level of vitamin D is associated with increased oral cancer risk. A high frequency of vitamin D deficiency and pleomorphism of the VDR have been reported in oral cancer patients. Poorly differentiated and aggressive OSCCs exhibit more CYP24A1 and VDR polymorphisms and less CYP27B1. Determination of the serum level of vitamin D and identification of VDR, CYP24A1, and CYP27B1 in oral cancer cells may be of significant prognostic value in oral cancer patients and may significantly improve the management of head and neck cancers.