OBJECTIVES: This systematic review and meta-analysis aimed to compare the anesthetic efficacy of 4% articaine buccal infiltration (BI) with 2% lidocaine inferior alveolar nerve block (IANB) for mandibular first molars with symptomatic irreversible pulpitis. METHODS: Randomized clinical trials (RCTs) comparing the anesthetic efficiency of one cartridge of 4% articaine BI (as the primary injection) with one cartridge of 2% lidocaine IANB in permanent first mandibular molars with symptomatic irreversible pulpitis were searched in five databases. The risk of bias (RoB) was evaluated using the RoB2 (Cochrane Risk of Bias Tool). A fixed-effects meta-analysis was performed using STATA software. The certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach. RESULTS: Out of 780 records, five RCTs were included. The meta-analysis revealed no significant difference in the success rates of articaine BI and lidocaine IANB [Risk ratio (RR) = 1.06, 95% confidence interval (CI) = (0.93, 1.20), I CONCLUSIONS: The moderate certainty of evidence suggests that the anesthetic efficacy of 4% articaine BI is comparable to 2% lidocaine IANB for mandibular first molars with symptomatic irreversible pulpitis. However, more clinical trials are needed. CLINICAL RELEVANCE: BI with 4% articaine for mandibular first molars with symptomatic irreversible pulpitis can be an alternative for clinicians compared with 2% lidocaine IANB.