Introduction: Achieving profound pulpal anesthesia can be difficult in patients with symptomatic irreversible pulpitis. This study provides a systematic review and meta-analysis to address the population, intervention, comparison, outcome (PICO) question: in adults with symptomatic irreversible pulpitis who are undergoing endodontic treatment, what is the comparative efficacy of articaine compared with lidocaine in reducing pain and incidence of adverse events? Methods: A protocol was prepared and registered on PROSPERO. Electronic searches were conducted in MEDLINE, Scopus, Cochrane Library, and ClinicalTrials.gov by using strict inclusion and exclusion criteria. Two independent reviewers assessed eligibility for inclusion and quality. Weighted anesthesia success rates and 95% confidence intervals (CIs) were estimated and compared by using a random-effects model. Results: Two hundred seventy-five studies were initially identified from the search; 10 double-blind, randomized clinical trials met the inclusion criteria. For combined studies, articaine was more likely than lidocaine to achieve successful anesthesia (odds ratio [OR], 2.21; 95% Cl, 1.41-3.47; P =.0006; I-2 = 40%). Maxillary infiltration subgroup analysis showed no significant difference between articaine and lidocaine (OR, 3.99; 95% CI, 0.50-31.62; P=.19; I-2 = 59%). For combined mandibular anesthesia studies articaine was superior to lidocaine (OR, 2.20; 95% CI, 1.40-3.44; P =.0006; I-2 = 30%), with further subgroup analysis showing no difference for mandibular block anesthesia (OR, 1.44; 95% Cl, 0.87-2.38; P =.16; I-2 = 0%). When used for supplemental infiltration after successful mandibular block anesthesia, articaine was significantly more effective than lidocaine (OR, 3.55; 95% CI, 1.97-6.39; P <.0001; I-2 = 9%). There were no reports of adverse events. Conclusions: This systematic review of double-blind, randomized clinical trials provides level 1 evidence to support the use of articaine for patients with symptomatic irreversible pulpitis. There is a significant advantage to using articaine over lidocaine for supplementary infiltration after mandibular block anesthesia but no advantage when used for mandibular block anesthesia alone or for maxillary infiltration.