Background: Oral potentially malignant disorders (OPMDs) and oral cancer (OC) are preventable oral mucosal diseases prevalent in Asian region. This epidemiological study aims to identify oral potentially malignant disorders (OPMDs) and oral cancer (OC), confirm histopathologically, and treat or refer these cases among the population of Eastern Development Region (EDR) of Nepal. It also attempts to assess the risk factors associated in order to compare dose–response measurements of oral habits in these patients. Methods: Cross-sectional epidemiological study was conducted over a period of 2 years in 16 districts of EDR. A total of 3,200 people were screened. A brief history was taken and visual screening examination was conducted in two phases as described by British Columbia Oral Cancer Prevention Program. Suspicious oral lesions were biopsied either by punch or scalpel after toluidine blue staining. Tissue specimen was transported to the institutional lab for histopathological processing. The reports were sent to the patients through the local leaders or organizations. Results: More than 40% of the study population either chewed areca nut and/or tobacco. Eighteen percent were smokers. OPMDs were prevalent among 468 study population with male-female ratio of 3:1. Tobacco pouch keratosis (50.4%) was the most prevalent OPMD, followed by OSF (29.1%). Fifty-two had squamous cell carcinoma and 8 had verrucous carcinoma. Conclusion: Chewing areca nut, tobacco, commercial areca nut/tobacco preparation and smoking being the major risk factors, there is high prevalence of oral cancer and OPMDs in the EDR of Nepal.