Purpose: Evaluate efficacy and safety of onabotulinumtoxinA compared with placebo for treating masseter muscle prominence (MMP). Methods: Adults with bilateral grade 4 (Marked) or 5 (Very marked) MMP on the 5-grade clinician-assessed MMP Scale (MMPS) received onabotulinumtoxinA 72 U, 48 U, or placebo. Primary efficacy endpoint was participants achieving MMPS grade ≤3 at day 90. Participants with grade ≤3 for the MMPS and Participant MMPS (MMPS-P), and participants achieving grade ≥2 in the Participant Self-Assessment of Change (PSAC), were evaluated until day 180. Results: Of 150 participants randomized, 34 (22.7%) discontinued (12 [8.0%] due to COVID-19). The modified intent-to-treat population included 145 participants (mean age, 39.3 years; mean BMI, 24.1 kg/m2; 89.7% female; 75.9% White). MMPS and MMPS-P responder rates were higher for onabotulinumtoxinA 72 U and 48 U than placebo at days 90 (MMPS: 91.3% and 90.6% vs 21.7%; MMPS-P: 93.5% and 96.2% vs 47.8%; both P<0.0001) and 180 (MMPS: 71.7% and 56.6% vs 26.1%; MMPS-P: 87.0% and 86.8% vs 60.9%; both P<0.01). More onabotulinumtoxinA 72 U and 48 U participants achieved PSAC grade ≥2 than placebo at days 90 (73.9% and 90.6% vs 21.7%; P<0.0001) and 180 (76.1% and 66.0% vs 28.3%; P<0.001). Treatment-related adverse events occurred in onabotulinumtoxinA 72 U and 48 U groups (12.2% and 9.4%) vs none in placebo; the majority were mild in severity. Conclusion: A single treatment of onabotulinumtoxinA (72 U and 48 U) reduced MMP and improved lower face contour for up to 6 months. Both dose groups demonstrated favorable safety profiles.