BACKGROUND: Oral potentially malignant disorders (OPMDs) constitute the most important precursors of oral cancer. Histopathological examination of a biopsy from a clinically suspicious lesion is still the gold standard for the diagnosis of oral cancer. Adjunctive techniques such as autofluorescence, toluidine blue (TB), and others have been evaluated among high-risk individuals such as chronic tobacco chewers or in patients with suspicious lesions. However, evaluation of these noninvasive adjunctive techniques has not been performed in primary health care settings. Since the first point-of-contact of individuals living in rural and semiurban areas are the primary health care workers, evaluation of these noninvasive adjuncts is likely to assist and strengthen the population-wide oral cancer screening in high-burden countries such as India. OBJECTIVE: This prospective longitudinal study aims to evaluate the noninvasive adjuncts in oral cancer screening in the field settings, specifically in detecting foci of oral cancers in various OPMDs. METHODS: After staff recruitment and training, we shall conduct oral cancer screening camps in the community for the recruitment of individuals with OPMDs after obtaining informed consent. All patients with OPMD shall undergo further screening via autofluorescence and TB staining for detection of lesions suspicious of oral cancer. Sensitivity, specificity, and negative and positive predictive values of these adjunctive techniques (autofluorescence and TB) in the detection of oral cancer shall be calculated using biopsy as the gold standard. In addition, this study will also focus on the validation of the 2022 consensus guidelines on risk-based stratification and appropriate management protocols for the OPMDs at the primary and referral health care centers. Our primary outcome is the diagnostic use of autofluorescence and TB in oral cancer detection among OPMDs as well as the robustness of the risk-based management protocols for these patients. RESULTS: Participant recruitment has been initiated at all sites. Staff recruitment and training in the oral visual examination have been conducted. Procurement of the autofluorescence device is in progress. All the study sites have begun conducting oral screening camps. CONCLUSIONS: The results of this study shall provide robust evidence for the diagnostic use of autofluorescence and TB staining in early oral cancer detection among patients with OPMD. The use of these noninvasive adjuncts by primary health care providers can significantly improve oral cancer screening in our country. The validation of risk-based stratification and management of patients with OPMD shall assist in the refinement of the national guidelines for these interventions. This study has been approved by the respective ethics committee of ICMR-National Institute of Cancer Prevention and Research and the collaborating institutes. The findings of this study shall be disseminated through scientific publications in peer-reviewed journals as well as meetings with the concerned stakeholders at the district and state health departments. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/66285.