Aim The aim of this study was to assess inferior alveolar nerve block (IANB) success of 2% mepivacaine (Scandonest 2%, Septodont, France) and 4% articaine (Septanest 4%, Septodont) in patients with symptomatic irreversible pulpitis (SIP) in mandibular molars during access cavity preparation and instrumentation. Methodology Three hundred and thirty patients with moderate‐to‐severe pain in mandibular molars with SIP randomly received either 3.6 ml 2% mepivacaine hydrochloride with 1:100 000 adrenalin or 3.4 ml 4% articaine hydrochloride with 1:100 000 adrenalin (n = 165). Intraoperative pain (IOP) intensity was assessed during access cavity preparation and canal instrumentation using 11‐point Numerical Rating Scale (NRS). Overall success was considered if the patient felt no‐to‐mild pain without the need for supplemental anaesthesia throughout treatment; the incidence of need for supplemental anaesthesia was also recorded. Data were statistically analysed using Mann–Whitney U‐ and Chi‐squared (χ2) tests. Relative risk (RR) and 95% confidence interval (CI) of anaesthetic failure were calculated. The effect of pre‐disposing factors on outcome variables was assessed using multivariable regression analyses. None of the participants reported any adverse effects. Results Baseline variables were balanced between groups (p > .05). The IOP intensity during access cavity preparation and canal instrumentation was similar for both groups (p > .05). IOP intensity was associated with preoperative pain intensity and tooth type (p < .05). Overall anaesthetic success rate was 35.8% for mepivacaine and 41.2% for articaine (p > .05) with a relative risk of failure [95% CI] 1.09 [0.92, 1.30]. The need for supplemental anaesthesia occurred 43.6% and 38.2% with mepivacaine and articaine respectively (p > .05; RR [95% CI]: 1.14 [0.88, 1.48]). Preoperative pain level and age were associated with the need for supplemental anaesthesia. Conclusions 2% mepivacaine and 4% articaine demonstrate similar IANB success rates for mandibular molars with SIP. Intraoperative pain experience during endodontic treatment can be associated with preoperative pain, tooth type and age.