The efficacy of preemptive analgesia in managing postoperative pain remains controversial. The aim of this study was to compare the efficacy of intravenous (IV) acetaminophen administered before or immediately after the surgical extraction of an impacted mandibular third molar. This prospective randomized clinical trial included 120 patients. The patients were assigned to one of three groups: the preoperative-treatment group (pre-group), which received 1000 mg of IV acetaminophen 20 min before surgery; the postoperative-treatment group (post-group), which received 1000 mg of IV acetaminophen after surgery; the no-treatment group (control-group), which did not receive any analgesic. Rescue analgesic (60 mg loxoprofen) was issued to each patient, with instructions on self-administration if needed. For the rescue medication usage, the time of first loxoprofen usage and the total amount of loxoprofen consumption were obtained for a 17-hour period after surgery. We measured pain using the visual analogue scale at 1 hour and at 2, 3, 4, 5, and 15 hours after surgery. There was no significant difference in pain level among the three groups at any time interval. However, the pre-group demonstrated significantly lower rescue analgesic consumption and longer time until initial administration. Administration of IV acetaminophen before third molar surgery provides more effective pain control than postoperative administration and no treatment.