Introduction: Recurrent aphthous stomatitis (RAS) is one of the most common ulcerative diseases affecting the general population. The present study aimed to evaluate the clinical efficiency of 0.5% minocycline mouth rinse prescribed along with the topical anesthetic gel and vitamin supplement over the topical anesthetic gel and vitamin supplement prescribed alone for treating RAS. Materials and Methods: A total of 60 participants were randomly divided into two groups—experimental group: 0.5% minocycline mouth rinse prescribed along with vitamin supplement and topical anesthetic gel; and control group: vitamin supplement and topical anesthetic gel alone. The pain symptoms were evaluated using the VAS scores at baseline and first follow-up visits. The data were analyzed using Student's t test. Results: A significant reduction in the pain scores was observed in participants using the 0.5% minocycline mouth rinse prescribed along with vitamin supplement and topical anesthetic gel on the first follow-up visit (P = < 0.001). Conclusion: The 0.5% minocycline mouth rinse prescribed along with vitamin supplement and topical anesthetic gel had shown more reduction in the pain symptoms when compared to topical anesthetic gel and vitamin supplement prescribed alone for the treatment of RAS.