Semaglutide treatment caused significant skeletal muscle loss alongside fat reduction in obese mice, with muscle strength declining and atrophy-related genes becoming elevated. Co-administration of β-hydroxybutyrate-generating ketone esters completely prevented this muscle wasting while preserving the drug's fat loss benefits. The protective mechanism involved maintaining mitochondrial gene expression and blocking atrophy signaling pathways that semaglutide typically disrupts. This finding addresses a critical clinical concern with GLP-1 receptor agonists like Ozempic and Wegovy, where nearly half of weight loss comes from muscle rather than fat. Such muscle loss threatens long-term metabolic health, mobility, and aging outcomes. The mouse model mirrors human observations of sarcopenia during GLP-1 therapy, making these results highly translatable. Ketone supplementation represents a potentially game-changing intervention that could transform how we approach GLP-1-based obesity treatment. Rather than accepting muscle loss as an inevitable trade-off, clinicians might soon combine these therapies to achieve ideal body recomposition. However, the three-week study duration and animal model limit immediate clinical application. Human trials are essential to confirm these protective effects and establish optimal ketone ester dosing protocols for preserving muscle during pharmaceutical weight loss.