Introduction: Oral cancer is one of the causes of major morbidity and mortality in the world although incidence varies in the different geographical locations and races. Advances in molecular biology and cancer research have allowed elucidating serum biomarkers to improve diagnostic methods. The aim of this article systematic review is to highlight the utility and clinical value of serum biomarkers in the diagnosis and prognosis of oral cancer. Material and Methods: A systematic literature review using PubMed (MEDLINE databases) revealed a total of 140 articles related to this topic. Of those articles, 29 were included in the final review. We included articles published in English in the last five years, developed in human as cases and controls studies, retrospective or prospective studies and specific studies that analyzed a certain biomarker in serum. Results: All of the studies include in this systematic review found significant differences in patients. Of those articles included, 2 used biomarkers to determinate cancerous phenotype, 11 mentioned their results were associated with worse prognosis and overall survival, 4 correlated biomarker concentration to clinical stages, 4 concluded it could be a helpful in diagnosis and 8 studies did not find a clear utility of the analysed biomarker. Due to differences in the presentation of data, meta-analysis was not possible. Conclusions: Biomarker use for diagnosis and prognosis is supported by clinical and scientific evidence is relevant. Nevertheless, after selecting a certain biomarker, monitoring protocols should be established in oral and maxillofacial surgeons teams so as we have a correct understanding of biological values.