Background: Oral Submucous Fibrosis is a potentially malignant disorder well known for its chronic and resistant nature. The conservative drug treatment that is currently available for this disorder is clearly inadequate. The main goal of the treatment of OSMF is to reduce trismus and burning sensation. The large number of treatment modalities have been tried both non-surgical and surgical approach. Aim: To compare the efficacy of treatment of Pindborg stage II, OSMF with and without lycopene in patient under intralesional dexamethasone and hyaluronidase therapy. Methodology: The present study included clinically diagnosed OSMF patient (stage II) and interincisal distance of less than 30mm. Complete case history was recorded with thorough clinical examination using specially designed case history format. The patients were randomly divided into 2 groups of 50 each. Group I received oral Lycopene capsules along with weekly intra-lesional injections of Dexamethasone (2mg/ml) & Hyaluronidase 1500 IU, Group II received, intralesional injection of dexamethasone (2mg/ml) and hyaluronidase (1500 IU). Difference between two groups was determined using student t-test and the level of significance was set at p < 0.05. Results: There was significant increase in mouth opening and reduction in burning sensation among Group I patients and the results were statistically significant. Conclusion: Lycopene in combination with intralesional steroids and Hyaluronidase, is highly efficacious in improving the mouth opening and reducing other symptoms in patients with Oral Submucous Fibrosis.