Piqueras-Sanchiz, F, Cornejo-Daza, PJ, Sánchez-Valdepeñas, J, Bachero-Mena, B, Sánchez-Moreno, M, Martín-Rodríguez, S, García-García, Ó, and Pareja-Blanco, F. Acute Mechanical, Neuromuscular, and Metabolic Responses to Different Set Configurations in Resistance Training. J Strength Cond Res XX(X): 000–000, 2021—The aim of this study was to investigate the effect of set configuration on mechanical performance, neuromuscular activity, metabolic response, and muscle contractile properties. Sixteen strength-trained men performed 2 training sessions in the squat exercise consisting of (a) 3 sets of 8 repetitions with 5 minutes rest between sets (3 × 8) and (b) 6 sets of 4 repetitions with 2 minutes rest between sets (6 × 4). Training intensity (75% one repetition maximum), total volume (24 repetitions), total rest (10 minutes), and training density were equalized between protocols. A battery of tests was performed before and after each protocol: (a) tensiomyography (TMG), (b) blood lactate and ammonia concentration, (c) countermovement jump, and (d) maximal voluntary isometric contraction in the squat exercise. Force, velocity, and power output values, along with electromyography data, were recorded for every repetition throughout each protocol. The 6 × 4 protocol resulted in greater mechanical performance (i.e., force, velocity, and power) and lower neuromuscular markers of fatigue (i.e., lower root mean square and higher median frequency) during the exercise compared with 3 × 8, particularly for the last repetitions of each set. The 3 × 8 protocol induced greater lactate and ammonia concentrations, greater reductions in jump height, and greater impairments in TMG-derived velocity of deformation after exercise than 6 × 4. Therefore, implementing lower-repetition sets with shorter and more frequent interset rest intervals attenuates impairments in mechanical performance, especially in the final repetitions of each set. These effects may be mediated by lower neuromuscular alterations, reduced metabolic stress, and better maintained muscle contractile properties.