This study aimed to compare mechanical, metabolic, and perceptual responses between two traditional (TR) and four cluster (CL) set configurations. In a counterbalanced randomized order, 11 men were tested with the following protocols in separate sessions (sets × repetitions [inter-repetition rest]): TR1: 3×10 [0-s]; TR2: 6×5 [0-s]; CL1: 3×10 [10-s]; CL2: 3×10 [15-s]; CL3: 3×10 [30-s]); CL4: 1×30 [15-s]). The exercise (full-squat), number of repetitions (30), inter-set rest (5 min), and resistance applied (10RM) was the same for all set configurations. Mechanical fatigue was quantified by measuring the mean propulsive velocity during each repetition, and the change in countermovement jump height observed after each set and after the whole training session. Metabolic and perceptual fatigue were assessed via the blood lactate concentration and the OMNI perceived exertion scale measured after each training set, respectively. The mechanical, metabolic, and perceptual measures of fatigue were always significantly higher for the TR1 set configuration. The two set configurations that most minimized the mechanical measures of fatigue were CL2 and CL3. Perceived fatigue did not differ between the TR2, CL1, CL2 and CL3 set configurations. The lowest lactate concentration was observed in the CL3 set configuration. Therefore, both the CL2 and CL3 set configurations can be recommended because they maximize mechanical performance. However, the CL2 set configuration presents two main advantages with respect to CL3: (1) it reduces training session duration, and (2) it promotes higher metabolic stress, which to some extent may be beneficial for inducing muscle strength and hypertrophy gains.