Objectives Speed of onset can be critical to an analgesic’s efficacy treating acute pain. To enhance onset, a new oral acetaminophen formulation intended to be fast acting was developed. Two studies evaluated the analgesic onset, efficacy, and safety of this fast-acting acetaminophen (FA-acetaminophen) tablet relative to commercial acetaminophen caplets (ES-acetaminophen) and commercial ibuprofen liquid-filled gelatin capsules (LG-ibuprofen). Methods Two single-center, single-dose, inpatient, randomized, double-blind, triple-dummy, placebo-controlled, parallel group design clinical trials were conducted using the postoperative dental impaction pain model. Subjects were healthy men and women aged 17–50 years experiencing moderate-to-severe pain after surgical extraction of at least three impacted third molars. In both studies, four treatment groups were evaluated: 1,000 mg acetaminophen as two 500 mg FA-acetaminophen tablets, 1,000 mg as two 500 mg ES-acetaminophen caplets, 400 mg ibuprofen as two 200 mg LG-ibuprofen capsules, and placebo. To maintain blinding, each subject received six units of study medication. Times to confirmed perceptible pain relief (TCPR) and meaningful pain relief (TMPR) were obtained using the double-stopwatch method. Pain intensity and relief were measured over 6 h following drug administration using a 0–10 numerical rating scale. Time to use of rescue medication (naproxen sodium) and subject global evaluations of study medications at 6 h were collected. Pharmacokinetic blood sampling and safety assessments were performed. Results Studies 1 and 2 enrolled 240 and 420 subjects, respectively. No clinically important differences among treatment groups were observed for any demographic or baseline characteristics. Efficacy results showed all active treatments statistically superior to placebo. In Study 1, TCPR was statistically significantly shorter for FA-acetaminophen compared to ES-acetaminophen and LG-ibuprofen. In Study 2, no statistically significant differences in TCPR were noted across the active treatment groups. In Study 1, FA-acetaminophen 1,000 mg provided significantly shorter TMPR compared with LG-ibuprofen but not compared with ES-acetaminophen. In Study 2, no significant differences in TMPR were noted across the active treatment groups. In both Study 1 and 2 at 15 min after administration of study drug, PID and PAR scores were greater for FA-acetaminophen than LG-ibuprofen. Conclusions Both studies suggested FA-acetaminophen had faster onset of action compared to ES-acetaminophen and LG-Ibuprofen. In light of the difference in TCPR and TMPR results between Study 1 and 2, an additional study is needed to further investigate time to analgesic onset of FA-acetaminophen compared with ES-acetaminophen and LG-Ibuprofen. Study registry numbers Study 1: NCT02735122; Study 2: NCT03224403