Aims and Objectives: Copper (Cu) and Zinc (Zn) are the important trace elements that play an important role in various functions of the human body at cellular and molecular level. The purpose of this study was to assess the alterations in serum Cu and Zn levels in oral potentially malignant disorders (OPMDs) and to correlate the variations with the severity and progression of the OPMDs. Materials and Methods: In this institution-based study, 20 of each clinically diagnosed and histopathologically proven cases of leukoplakia (Group 1), oral lichen planus (Group 2), clinically diagnosed cases of oral submucous fibrosis (OSMF) and 20 healthy age and sex matched controls were taken based on the clinical staging. Clinical examination of the selected subjects was carried out and an informed consent was obtained, following which blood samples were collected from the participants. After serum separation, Cu and Zn levels were analyzed using the colorimetric method. Data were sent for the statistical analysis using the Statistical Package for the Social Sciences (SPSS) software, version 21.0. Results: Serum copper levels were increased and zinc levels were decreased in patients with OPMDs when compared to that in the control group. However, gradual increase in the levels of serum Cu was found with the advancing stages of OSMF. No statistical significant relation was observed in the levels of serum Zn with the disease progression in OSMF. Conclusion: Serum Cu and Zn levels can have diagnostic significance in early evaluation of OPMDs. Increased serum Cu levels can be used as a marker of disease progression and severity in OSMF.