Oral squamous cell carcinoma (OSCC) and potentially malignant oral disorders (OPMDs) could be associated with low levels of vitamin D. This systematic review aimed to determine the relationship between serum levels of vitamin D with OPMDs and OSCC. This review was conducted according to Cochrane guidelines (PROSPERO CRD42020207382) on literature retrieved from the PubMed, Cochrane, and Web of Science databases. The antecedents extracted were study design, methodology, sample (country, number of patients, age, and sex), oral manifestations (type of lesion, location, prevalence, and follow-up), serum vitamin D levels or use of vitamin D supplements, results, and conclusions. Twelve articles were selected. Some of the most relevant findings were alterations in vitamin D could favor the progress of OPMDs to OSCC. Higher levels of vitamin D can increase levels of anti-inflammatory mediators, CD4+ T lymphocytes and CD8+ T lymphocytes and CD3+ T lymphocytes in intratumoral tissue. The normalization of vitamin D levels in patients with OSCC can increased cytotoxic activity of natural killer cells, favoring antitumor immune response. Vitamin D supplemented can lower adverse effects associated with chemotherapy like mucositis and pain. Tobacco can increase risk of developing OSCC altering vitamin D levels. Hypovitaminosis D could increase risk of developing OSCC from OPMDs, thus altering the immune response and it is associated with a lower survival rate in patients with OSCC, a greater recurrence of tumors in patients who underwent surgical treatment, and an increase in adverse reactions to chemotherapy. The use of vitamin D supplements can be a complement to primary therapy to prevent the recurrence of lesions and reduce adverse events associated with treatment.