Background- Oral leukoplakia is a very common premalignant condition that characterizes variable clinical manifestations with a significant potential for malignant transformation. In its diagnosis and treatment, diverse approaches are given such as surgical, pharmacological, and adjunctive treatments. To date, little consensus exists regarding the most appropriate diagnostic and therapeutic strategies. It is in this context that the systematic review of available evidence is needed. Methods- This systematic review will be undertaken based on the PECOS framework for defining the inclusion criteria. Selection of studies Studies evaluating diagnostic or therapeutic interventions for oral leukoplakia were selected, including randomized controlled trials, cohort studies, and observational studies. The search was performed cross five databases: PubMed, Scopus, Web of Science, Embase, and Cochrane Library, with the use of Boolean operators and MeSH keywords. An extraction table is used to summarize the study characteristics, methods of diagnosis, intervention utilized, outcomes, and statistical findings. Bias was evaluated with the ROBINS-I for non-randomised studies and the Cochrane RoB 2.0 tool for randomized trials. Results- Eight studies fulfilled the inclusion criteria. The number of sample participants varied between 18 and 4886 subjects. Routine biopsies were crucial for monitoring of the dysplastic lesions. Cancer progression risks were highly increased in biopsied groups: SIR = 40.8, 95% CI: 34.8–47.6; HR = 2.38, 95% CI: 1.73–3.28. Therapeutic treatments like curcumin resulted in increased clinical response rates (67.5% vs 55.3%, p=0.03) and AFL-PDT showed a response rate of 87.5%, but recurrence was site-specific with a relative risk of OR: 1.64 (p<0.001). Beta-carotene and Vitamin C showed minimal benefit, where remission rates in treated groups were 21.1% compared with 4.8% controls (p=0.172). Diagnostic and treatment practice deviated significantly as 83% of doctors made it a regular procedure to take biopsies (p<0.001). Pain relief was achieved through laser-assisted interventions, which significantly alleviated symptoms (p<0.05). Conclusion- The review noted heterogeneity in both diagnosis and treatment of oral leukoplakia. Even the promising results seen with treatments such as curcumin or AFL-PDT, few chemopreventive agents showed a weak efficacy level; hence, there is a need for stronger evidence. Routine biopsies were performed for risk stratification, and important geographic variability in practice was recorded. These findings underscore the need for standardized guidelines to improve the outcomes in patients.