Zynamite PX, a mango leaf extract combined with quercetin, enhances exercise performance by unknown molecular mechanisms. Twenty-five volunteers were assigned to a control (17 males) or supplementation group (8 males, receiving 140 mg of Zynamite + 140 mg quercetin/8 h for 2 days). Then, they performed incremental exercise to exhaustion (IE) followed by occlusion of the circulation in one leg for 60 s. Afterwards, the cuff was released, and a 30 s sprint was performed, followed by 90 s circulatory occlusion (same leg). muscle biopsies were obtained at baseline, 20 s after IE (occluded leg) and 10 s after Wingate (occluded leg), and bilaterally at 90 s and 30 min post exercise. Compared to the controls, the Zynamite PX group showed increased basal protein expression of Thr-CaMKIIδ (2-fold, = 0.007) and Ser-GSK3β (1.3-fold, = 0.005) and a non-significant increase of total NRF2 (1.7-fold, = 0.099) and Ser-NRF2 (1.2-fold, = 0.061). In the controls, there was upregulation with exercise and recovery of total NRF2, catalase, glutathione reductase, and Thr-CaMKIIδ (1.2-2.9-fold, all < 0.05), which was not observed in the Zynamite PX group. In conclusion, Zynamite PX elicits muscle signaling changes in resting skeletal muscle resembling those described for exercise training and partly abrogates the stress kinases responses to exercise as observed in trained muscles.