Objective To evaluate the anesthetic efficacy of 4% articaine with 1:100,000 epinephrine via primary intraosseous (IO) injection with the QuickSleeper device vs inferior alveolar nerve block (IANB) for mandibular first molars diagnosed with symptomatic irreversible pulpitis (SIP). Methods Sixty-four patients with a first mandibular molar with SIP were randomly divided into 2 groups: IO (n = 32) and IANB (n = 32). Each received either an IO injection with the 5th generation QuickSleeper device or a conventional IANB with 1.7 mL 4% articaine with 1:100,000 epinephrine. Success was defined as no/mild pain upon the access cavity preparation and initial filing. Injection pain, anesthetic onset, heart rate (HR) change, HR recovery time, and duration of anesthesia were also recorded and analyzed. Results The success rates were 40.6% for IANB and 81.2% for IO (P < .001). IO exhibited a significantly lower injection pain (P = .027), a shorter onset of action (P < .001), a greater heart rate increase (P < .001), a faster heart rate recovery time (P < .001), and a shorter duration of action (P < .001) vs IANB. Conclusion Primary IO anesthesia using the fifth generation of the QuickSleeper device was more successful than IANB when using 4% articaine with 1:100,000 epinephrine to anesthetize mandibular first molars with SIP. The QuickSleeper device appeared to be a viable alternative to IANB for mandibular anesthesia.