The study aimed to evaluate the impact of ischemia, used only before particular sets of a lower limb resistance exercise on power output. Ten healthy resistance-trained males (age = 26 ± 6 years; body mass = 90 ± 9 kg; training experience = 9 ± 7 years) performed two experimental sessions (with ischemia; control without ischemia) following a randomized crossover design. During the ischemic condition, the cuffs were inflated to 60% of arterial occlusion pressure. The cuffs were applied before each set for 4.5 min and released 30 s before the start of the set as the reperfusion (4.5 min ischemia + 0.5 min reperfusion). In the control condition, ischemia was not applied. During the experimental sessions, the subjects performed the Keiser machine squat exercise protocol which consisted of 5 sets of two repetitions, at a load of 60% of one-repetition maximum (1RM), with 5 min rest intervals between sets. The repetitions were performed with maximal velocity. The two-way repeated-measures ANOVA showed a statistically significant interaction effect for power output (p < 0.01; η2 = 0.26). There was also a statistically significant main effect of condition for power output (p = 0.02; η2 = 0.40). The post hoc analysis for interaction did not show significant differences between conditions in particular sets. The post hoc analysis for the main effect of the condition revealed that power output was significantly lower in the control group compared to the group where ischemic was used (p = 0.02). The t-test comparisons for particular sets showed a significant lower power output in set 3 (p = 0.03); set 4 (p < 0.01) and set 5 (p < 0.01) for the control condition when compared to the ischemic condition. The results indicate that ischemia applied before each set and released 30 s prior to the start of the squat exercise did not increase power output performance. However, we observed a significantly lower decline in power for the ischemic condition (4.5 min ischemia + 0.5 min reperfusion) in sets 3–5 compared to the control condition. Thus repeated ischemia with reperfusion used between sets can be an effective form of performance enhancement by preventing or at least diminishing fatigue during resistance exercise.