Introduction: Optimal pain management of symptomatic pulpitis in formative years goes a long way in developing a positive dental attitude. Efforts should be made to increase the success of anesthesia, thus diminishing negative dental experiences. The aim of the study was to assess the efficacy of preemptive analgesia on the success of pulpal anesthesia following inferior alveolar nerve block (IANB) in children with symptomatic irreversible pulpitis and on reducing postendodontic pain. Materials and methods: The research design was an in vivo, three-group, parallel, quadruple-blind study. A total of 75 patients were randomly allocated to one of the three groups—group I: ibuprofen, group II: combination of ibuprofen and paracetamol, and group III: multivitamin (placebo). Premedication was given 45 minutes before treatment, and patients received IANB in a standardized manner. Pain during pulpectomy was recorded using the face, legs, activity, cry, consolability (FLACC) scale and postoperatively using Wong–Baker's pain rating scale (WBPRS) at 4, 12, and 24 hours. Success was measured if the pain felt was of no or mild intensity. Results: Success of IANB was 64% for ibuprofen, 72% for the combination group, and 40% for the placebo group, with no statistically significant difference between all groups (p = 0.06) on the FLACC scale. At 4 hours postoperatively, a significant difference (p = 0.02) was found among groups with more children experiencing no or mild pain in groups I and II and the highest number of rescue medications taken by the placebo group. Conclusion: Ibuprofen and a combination of ibuprofen and acetaminophen as preemptive analgesics had no significant effect on the success rate of IANB, although it was effective in reducing pain at 4 hours postoperatively.