Purpose: The aim was to compare changes in peripheral and cerebral oxygenation, as well as metabolic and performance responses during conditions of blood flow restriction (BFR, bilateral vascular occlusion at 0% vs. 45% of resting pulse elimination pressure) and systemic hypoxia ($∼$ 400 m, FIO2 20.9% vs. $∼$ 3800 m normobaric hypoxia, FIO2 13.1 ± 0.1%) during repeated sprint tests to exhaustion (RST) between leg- and arm-cycling exercises. Methods: Seven participants (26.6 ± 2.9 years old; 74.0 ± 13.1 kg; 1.76 ± 0.09 m) performed four sessions of RST (10-s maximal sprints with 20-s recovery until exhaustion) during both leg and arm cycling to measure power output and metabolic equivalents as well as oxygenation (near-infrared spectroscopy) of the muscle tissue and prefrontal cortex. Results: Mean power output was lower in arms than legs (316 ± 118 vs. 543 ± 127 W; p < 0.001) and there were no differences between conditions for a given limb. Arms demonstrated greater changes in concentration of deoxyhemoglobin (∆[HHb], − 9.1 ± 6.1 vs. − 6.5 ± 5.6 $μ$m) and total hemoglobin concentration (∆[tHb], 15.0 ± 10.8 vs. 11.9 ± 7.9 $μ$m), as well as the absolute maximum tissue saturation index (TSI, 62.0 ± 8.3 vs. 59.3 ± 8.1%) than legs, respectively (p < 0.001), demonstrating a greater capacity for oxygen extraction. Further, there were greater changes in tissue blood volume [tHb] during BFR only compared to all other conditions (p < 0.01 for all). Conclusions: The combination of BFR and/or hypoxia led to increased changes in [HHb] and [tHb] likely due to greater vascular resistance, to which arms were more responsive than legs.