Introduction: Post-endodontic pain is one of the main problems for both patients and dentists. The purpose of this study was to compare the effectiveness of premedication with indomethacin and ibuprofen for management of postoperative endodontic pain. Methods and Materials: In this clinical trial, mandibular molars with irreversible pulpitis were endodontically treated in 66 patients. The medicines were prepared similarly in the form of capsules containing 400 mg ibuprofen (group A), 25 mg indomethacin (group B) and placebo (group C). The patients were given one capsule 1 h before the start of treatment. Patients recorded their pain measured by a visual analogue scale (VAS) at medication time, during treatment and 8, 12 and 24 h after treatment. The data were analyzed using the chi-square, repeated measures ANOVA, paired t-test, Tamhane and Pearson correlation coefficient. Results: Ibuprofen and indomethacin significantly reduced the postoperative pain in comparison with placebo during treatment and 8 h after treatment; however, there were no significant differences between them 12 and 24 h after treatment. Conclusion: Premedication with ibuprofen and indomethacin can effectively control short term post-operative pain; the lower incidence of side effects and greater analgesic power of ibuprofen make it a superior choice.Keywords: Ibuprofen; Indomethacin; Irreversible Pulpitis; Non-Steroidal Anti-Inflammatory Drugs; Post-Endodontic Pai