The purpose of this study was to determine the influence of a comprehensive multi-component nutritional supplement on performance, hormonal, and metabolic responses to an acute bout of resistance exercise. Nine healthy subjects ingested either Muscle Fuel (MF) or a matched placebo (PL) for 7 days. Subjects then reported to the laboratory, ingested the corresponding supplement, and performed two consecutive days of heavy resistance exercise testing with associated blood draws. MF supplementation improved vertical jump (VJ) power output and the number of repetitions performed at 80% of one repetition maximum (1RM). Additionally, MF supplementation potentiated growth hormone (GH), testosterone, and insulin-like growth factor-1 responses to exercise. Concentrations of circulating myoglobin and creatine kinase (CK) were attenuated immediately following resistance exercise during the MF trial, indicating that MF partially mediated some form of exercise-induced muscle tissue damage. In summary MF enhanced performance and hormonal responses associated with an acute bout of resistance exercise. These responses indicate that MF supplementation augments the quality of an acute bout of resistance exercise thereby increasing the endocrine signaling and recovery following heavy resistance exercise.