Objective: The purpose of the present study was to assess effect of 4% articaine infiltration versus 2% lidocaine nerve block after premedication by ibuprofen on anesthetic efficacy in endodontic treatment of acute irreversible pulpitis in a randomized clinical trial (RCT). Participants and Methods: Fifty-two emergency patients diagnosed with symptomatic irreversible pulpitis in mandibular first molar, were randomly divided in lidocaine and articaine group. Patients were given a tablet of Ibuprofen 600 mg premedication one hour before administration of local anesthesia. Root canal treatment was performed in a single visit using Revo-S rotary system and sodium hypochlorite irrigation for cleaning and shaping. Obturation was carried out using lateral compaction technique and Resin sealer. Patients were instructed to rate any discomfort on the Numerical rating scale through access preparation, pulp extirpation and postoperatively. Pain intensity was assigned into 4 categorical scores: Score 1: none (0); Score (2): mild (1-3); Score 3: moderate (4-6); and Score 4: severe (7-10). In the current study, the primary outcome was the pain felt during access cavity preparation, as recorded by NRS and secondary outcomes were pain felt in radicular extirpation and postoperative pain. Success was defined as no/mild pain during access cavity preparation. The significance level was set at P ≤ 0.05.Results: There was no statistically significant difference in the percent of successful cases between lidocaine (38.5%, 61.5%) and articaine (50%, 73.1%) during access cavity preparation and cleaning and shaping, respectively, with P value ≤0.05.Conclusion: Articaine mandibular buccal infiltration can be a reliable alternative to inferior alveolar nerve block during emergency access cavity in mandibular molars with irreversible pulpitis.