The aim of this randomized clinical trial was to compare the success rate of three different anesthetic techniques in mandibular molars with symptomatic irreversible pulpitis. Ninety patients with symptomatic irreversible pulpitis in mandibular molars randomly received three anesthetic techniques. Group I: an inferior alveolar nerve block (IANB) of 2% lidocaine. Group II: IANB and buccal infiltration (BI) of 4% articaine. Group III: IANB + BI and intraseptal injection of articaine in each mesial and distal papilla. The pain (Heft-Parker visual analog scale (VAS)) and electric pulp tester (EPT) scores were recorded prior to (VAS1, EPT1) and after the injection and during access preparation (VAS2, EPT2). The success of anesthesia was defined as the ability to access the tooth with no or mild pain (VAS ≤ 54). The mean value for VAS2 was significantly less and the mean value for EPT2 was significantly more in groups II and III compared with group I. The success rates for groups I, II, and III were 30.33%, 66.66%, and 80.00% respectively. Also, differences of EPT2, VAS2, and success rates were statistically significant between groups II and III. Administration of articaine as a supplemental intraseptal and BI following IANB can be considered a more successful anesthetic technique in mandibular molars with symptomatic irreversible pulpitis compared with the conventional IANB and supplemental BI. The addition of an articaine intraseptal injection to IANB+BI technique may result in a significantly higher success rate of pulpal anesthesia in mandibular molars with symptomatic irreversible pulpitis.