Purpose: To assess tissue oxygenation, along with metabolic and physiological responses during blood flow restriction (BFR, bilateral vascular occlusion) and systemic hypoxia conditions during submaximal leg- versus arm-cycling exercise. Methods: In both legs and arms, 4 randomized sessions were performed (normoxia 400 m, fraction of inspired oxygen [FIO2] 20.9% and normobaric hypoxia 3800 m, FIO2 13.1% [0.1%]; combined with BFR at 0% and 45% of resting pulse elimination pressure). During each session, a single 6-minute steady-state submaximal exercise was performed to measure physiological changes and oxygenation (near-infrared spectroscopy) of the muscle tissue in both the vastus lateralis (legs) and biceps brachii (arms). Results: Total hemoglobin concentration ([tHb]) was 65% higher (P < .001) in arms versus legs, suggesting that arms had a greater blood perfusion capacity than legs. Furthermore, there were greater changes in tissue blood volume [tHb] during BFR compared with control conditions (P = .017, F = 5.45). The arms elicited 7% lower tissue saturation (P < .001) and were thus more sensitive to the hypoxia-induced reduction in oxygen supply than legs, no matter the condition. This indicates that legs and arms may elicit different regulatory hemodynamic mechanisms (ie, greater blood flow in arms) for limiting the decreased oxygen delivery during exercise with altered arterial oxygen content. Conclusions: The combination of BFR and/or hypoxia led to increased [tHb] in both limbs likely due to greater vascular resistance; further, arms were more responsive than legs. This possibly influences the maintenance of oxygen delivery and enhances perfusion pressure, suggesting greater vascular reactivity in arms than in legs.