Identifying oral dysplastic lesions with a high risk of malignant transformation may create opportunities for early therapeutic interventions. Several tissue biomarkers have been suggested to date as prognostic indicators of the progression of dysplastic lesions to oral cancer. We herein present a systematic review (PROSPERO CRD42018086476), with the aim of identifying, evaluating and summarizing evidence on prognostic biomarkers of progression to oral cancer in patients with dysplasia. A search through MEDLINE/PubMed and Scopus databases was performed. The review only included primary articles that reported risk values associated with malignancy after a multivariate analysis. The quality of the findings was analyzed using the Reporting Recommendations for Tumor Marker Prognostic Studies, and research trends were established using SciCurve Open. A total of 4 potential biomarkers were identified: Degree of dysplasia, and the proteins retinal dehydrogenase 1, prominin-1 and podoplanin. All 3 protein biomarkers have been recognized as cancer stem cell markers. The studies were of acceptable quality, although none included sample size determinations. Due to the lack of validation and follow-up studies, these biomarkers are considered to be in a discovery phase and require validation by prospective clinical trials. The present analysis indicated that there are currently insufficient data to include these biomarkers in the clinical decision-making process.