Background: Healing followed by the surgical removal of third molar is known to cause increased discomfort to the patients. Many theories and ideas have been idealized to reduce this discomfort. Traditionally, systemic antibiotics were used. But due to the phenomena of antibiotic resistance to multiple microorganisms we are constantly on the process of discovering new methods and modifying age-old methods for the better usage of antibiotics in future by either finding a supplement or an alternative. Ozone is one of such old methods which is found to be effective. It meets all the expectations as an alternative for antibiotics and also ful fills the application of it in the needed area alone thereby, restricting the systemic use of antibiotics. Platelet rich fibrin (PRF) is well known as the gold standard material for promoting healing.In this study, topical ozone gel and platelet-rich fibrin(PRF) are compared with the conventional method to evaluate their effectiveness in the healing of surgical extraction of impacted mandibular third molars. Materials and Methods: A double-blinded randomized controlled clinical trial was designed involving the patients who required removal of impacted mandibular third molars. The sample size was estimated as 60 individuals with 20 in each group. Of the study groups, one received topical ozone without post-operative systemic antibiotics, another received metronidazole with PRF while the control group received systemic antibiotics. All the groups were prescribed standard analgesics for 3 days. Postoperatively, the patients were reviewed at 24 hours, 3rd day and 7th day. Results: Data were collected and analysis involved independent sample ‘t’ test. The study groups, ozone gel application and metronidazole with PRF demonstrated statistically significant (p<0.05) reduction in post-operative pain, swelling, and incidence of alveolar osteitis with increased mouth opening. No adverse effects of ozone gel were observed in any of the patients. Conclusion: In this study, it is concluded, that ozone can be considered as a potent topical antibiotic with healing property and also as an adjunct analgesic.