Background/Objectives: Anabolic resistance is thought to underlie muscle loss in sarcopenia. Here, we investigated the adjuvant role of beta-hydroxy-beta-methylbutyrate (HMB), a leucine metabolite, on the acute muscle anabolic response to oral protein supplementation in older adults. Methods: A total of 24 community-dwelling older adults (68.5 ± 0.6 years; 13 men, 11 women) were randomized in a cross-over double-blind design to 40 g whey protein (Control) or 40 g whey protein with 3 g calcium–HMB (HMB). Subjects received a primed constant infusion of ¹³C₆ phenylalanine to assess muscle protein synthesis (MPS, by tracer incorporation in myofibrils) and muscle protein breakdown (MPB, via arterio-venous dilution) at baseline and post supplementation. Fasted and 3 h fed-state plasma HMB, aminoacidemia, rates of MPS, MPB, limb and muscle blood flow were measured. Results: In all subjects, both interventions displayed significant increases in MPS in response to feeding [fasted to 3 h-fed change (mean ± SEM, standard error of the mean). Males: control, +0.032 ± 0.006%.h⁻¹; HMB, +0.023 ± 0.004%.h⁻¹; females: control, +0.023 ± 0.006%.h⁻¹; HMB, +0.038 ± 0.006%.h⁻¹, p < 0.05]. In older women, the addition of HMB further enhanced the MPS response (fasted to 3 h-fed change, p = 0.0495) and area under the curve (p = 0.0364) versus protein alone. During the late-fed period, MPB significantly decreased in HMB versus control (p = 0.0298), and this was also observed when subjects were separated by sex (p = 0.0012). Conclusions: High-dose protein bolus feeding increased MPS in older adults. Surprisingly, 40 g whey did not maximize the anabolic response in older women, and HMB further increased the MPS feeding response to protein. HMB further suppressed the MPB feeding response over a longer period of time. Further work is needed to understand the apparent sexual dimorphic MPS response to high protein.