Objective To compare the effectiveness and complications of intraligamentary anesthesia (ILA) with conventional inferior alveolar nerve block (IANB) during injection and dental treatment of mandibular posterior teeth. Materials and methods In this randomized, prospective clinical trial, 72 patients (39 males, 33 females), scheduled for dental treatment of mandibular posterior teeth, were randomly allocated to ILA group (n = 35) received ILA injection or IANB group (n = 37) received the conventional IANB. Our primary outcome was to assess pain and stress (discomfort) during the injection and dental treatment, using the numeric rating scale (NRS) from 0 to 10 (0 = no pain, 10= the worst pain imaginable), whereas recording 24-h postoperative complications was our secondary outcomes. Results Patients in ILA group reported significantly less pain during injection when compared with IANB group (p = 0.03), while pain during dental treatment was similar in both groups (p = 0.2). Patients in both groups also reported similar law values of discomfort during treatment (p = 0.7). Although no signs of nerve contact or any other postoperative complications were observed, five patients in IANB group (none in ILA group) reported temporary irritations. Conclusion This study showed equivalent effectiveness of both intraligamentary anesthesia and conventional inferior alveolar nerve block, for pain control during routine dental treatment of mandibular posterior teeth. Nevertheless, ILA showed significantly less pain during injection. No major postoperative complications in both groups were observed. Clinical relevance ILA could be considered as an effective alternative for routine dental treatment. Trial registration NCT04563351