Uncoupling protein-3 (UCP3) is a mitochondria-regulatory protein with potential energy- homeostatic functions. This study explores the role of UCP3 in the regulation of muscle- and energy metabolism. UCP3 is critical for tuning substrate utilization, favoring lipid oxidation, particularly in conditions of high-fat availability. While UCP3 is non-essential for lipid oxidation during energy excess, it proves vital during fasting, indicating an energy-homeostatic trait. Preliminary evidence indicates UCP3' promotion of glucose uptake and oxidation, at least in conditions of high glucose/low fat availability. However, the dynamics of how fats and glucose differentially influence UCP3 remain undefined. UCP3 exhibits inducible proton transport and uncoupling activity, operating in a dual manner: a resting state with no/low activity and an activated state in the presence of activators. Uncoupling may enhance thermogenesis in specific conditions and in the presence of activators such as fatty acids, thyroid hormones, and catecholamines. This energy-dissipative activity adapts to varying energy availability, balancing energy dissipation with fatty acid oxidation to optimize whole-body energy homeostasis: fasting triggers UCP3 upregulation, enhancing lipid utilization while suppressing uncoupling. Additionally, UCP3 upregulation induces glucose and lipid disposal from the bloodstream and decreases tri-/diglyceride storage in muscle. This process improves mitochondrial functionality and insulin signaling, leading to enhanced systemic gluco-metabolic balance and protection from metabolic conditions. Reviewed evidence suggests that UCP3 plays a crucial role in adapting the system to changing energy conditions. However, the precise role of UCP3 in regulating metabolism requires further elucidation.