Background: This was a randomized controlled clinical trial that aimed to evaluate the anesthetic efficacy of 2% lidocaine combined with different concentrations of epinephrine (plain, 1:200,000 and 1:80,000) during endodontic treatment of maxillary molars with symptomatic irreversible pulpitis. Methods: The trial included 144 adult patients who were randomly allocated to three treatment groups. All patients received buccal-plus-palatal infiltration. After 10 min, pulp sensibility testing was performed using an electric pulp test (EPT). If a tooth responded positively, anesthesia was considered to have failed. In the case of a negative EPT response, endodontic access was initiated under rubber dam isolation. The success of anesthesia was defined as having a pain score less than 55 on the Heft Parker visual analog scale (HP VAS), which was categorized as ‘no pain’ or ‘faint/weak/mild’ pain on the HP VAS. Baseline pre-injection and post-injection maximum heart rates were recorded. The Pearson chi-square test was used to analyze the anesthetic success rates at 5% significance. Results: Plain 2% lidocaine and 2% lidocaine with 1:200,000 epinephrine and 1:80,000 epinephrine had anesthetic success rates of 18.75%, 72.9%, and 82.3%, respectively. Statistical analysis indicated significant differences between the groups (P < 0.001, χ2 = 47.5, df = 2). The maximum heart rate increase was seen with 2% lidocaine solution with epinephrine. Conclusion Adding epinephrine to 2% lidocaine significantly improves its anesthetic success rates during the root canal treatment of maxillary molars with symptomatic irreversible pulpitis.