This study explored the acute and delayed (24 and 48 hours after exercise) effects of a resistance training session leading to muscular failure. Eleven resistance-trained men completed a training session consisting on 3 sets of repetitions to failure during the back-squat exercise performed at the maximum possible speed with a load equivalent to a mean propulsive velocity (MPV) of 1 m·s−1 (≈60% of 1 repetition maximum). A number of mechanical (number of repetitions and starting MPV of the set, MPV achieved against the 1MPV load, countermovement jump [CMJ] height, and handgrip strength), metabolic (lactate, uric acid, and ammonia concentrations), and perceptual (OMNI-RES perceived exertion) variables were measured. The results revealed (a) a decrease of 38.7% in set 2 and 54.7% in set 3 of the number of repetitions performed compared with the first set (p < 0.05), (b) a reduction in the MPV of the repetitions and an increase in lactate concentration and OMNI-RES values with the succession of sets (p < 0.05), (c) comparable decrements in CMJ height after the 3 sets (25–32%), (d) a decrease in CMJ height (p < 0.05; 6.7–7.9%) and in the MPV attained against the 1MPV load (p < 0.05; 13–14%) after 24 and 48 hours of completing the training session, but no significant changes were observed in handgrip strength (p > 0.05; <2%), and (e) uric acid and ammonia concentrations above the basal levels (p < 0.05). The large decrements in mechanical performance together with the high metabolic stress discourage the frequent use of resistance training sessions leading to muscular failure.