This study aimed to compare the effectiveness of mepivacaine and lidocaine for pulpal anaesthesia and pain control when administered via an inferior alveolar nerve block during the root canal treatment of mandibular molars in patients with symptomatic irreversible pulpitis. A research protocol was developed and registered in PROSPERO. The systematic search was conducted during May 2017 in eight databases. The studies were selected based on inclusion and exclusion criteria. Two examiners analysed the sample independently, decided the eligibility for inclusion and classified the articles according to their quality. Statistical analysis was performed with Mantel-Haenszel and I-square (I2) tests considering a confidence interval of 95%. The initial sample consisted of 1130 articles, out of which four were eligible. The articles were published between 1993 and 2016. For both pulpal anaesthesia and pain control, there was no significant difference between mepivacaine and lidocaine (P = 0.843, I2 = 0%, and P = 0.183, I2 = 21.1%, respectively). Mepivacaine and lidocaine were similarly effective for pulpal anaesthesia and pain control after inferior alveolar nerve blocks for root canal treatment.