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Statement of the Problem: Considering side effects of non-steroidal anti-inflammatory drugs (NSAIDs), herbal medicine including Urtica dioica might help reduce the pain. Purpose: The present study aimed to compare the effects of premedication with essential oil of Urtica dioica and ibuprofen on post-endodontic pain. Materials and Method: The present randomized clinical trial study was conducted on 60 patients with symptomatic irreversible pulpitis of mandibular first or second molars. The patients were randomly assigned to three groups (n=20) for premedication with 400 mg ibuprofen, 400 mg essential oil of Urtica dioica (Netonal; Barij, Iran), and placebo. The medications were taken 30 minutes prior to the procedure. The patients' pain score was recorded before the intervention and treatment onset (Time1 or T1), after the intervention prior the treatment onset (10 minutes after anesthetic injection) (T2), upon completion of treatment (T3), and at 8 (T4), 12 (T5), and 24 hours after endodontic treatment (T6) using a visual analog scale (VAS) and Wong-Baker FACES Pain Rating Scale (WBS), and compared. Data were analyzed by Chi-square test, one-way and repeated measures analysis of variance (ANOVA), kruskal-wallis test, and LSD post-hoc test using IBM SPSS statistics version 21 with significance value of p< 0.05. Results: The pain score was not significantly different among the three groups at T1, T2 and T3 according to both scales (p> 0.05). On the other hand, significantly lower pain scores were recorded in ibuprofen and Urtica dioica groups at 8, 12, and 24 hours after treatment compared with the placebo group (p< 0.001). The pain score was not markedly different between the ibuprofen and Urtica dioica groups (p> 0.05). Conclusion: It seems that analgesic effect of premedication with leaf extract of Urtica dioica is the same as ibuprofen. Further studies are warranted to find the optimal dosage of Urtica dioica for widespread use. [ABSTRACT FROM AUTHOR]