Purpose Integrated physiological responses during maximal whole-body exercise, such as cycling, under additive hypoxemia (anemia + hypoxia) are not adequately studied. Therefore, we investigated cardiovascular, muscular and cerebral oxygenation responses in chronic mildly iron-deficient and control women under normoxic and moderate hypoxic conditions during maximal whole-body exercise. Methods In a randomized and counterbalanced order, 16 females performed incremental exercise to exhaustion under normoxia (N; FIO2:20.94%) and hypoxia (H; FIO2:13.6%). The participants were divided into two groups matched for age and anthropometric characteristics, but intentionally varying in [Hb] (p textless 0.001) and V̇O2max (p textless 0.01); iron-deficient (A; n = 8; [Hb]:11.3 ± 0.4 g/dl; V̇O2max:37.3 ± 2.8 ml/kg/min) and healthy controls (C; n = 8; [Hb]:13.3 ± 0.4 g/dl; V̇O2max:40.8 ± 1.9 ml/kg/min). Results During exercise in hypoxia compared to normoxia, the A exhibited greater decrement in V̇O2max (5.0%; p = 0.02) and peak power output (5.4%; p = 0.004) than C. Maximal mean arterial pressure was reduced (p textless 0.05) due to lower total peripheral resistance (p textless 0.05) and unchanged maximal cardiac output (p textgreater 0.05). Enhanced O2 utilization under H was observed only in C, based on ΔHHb (p textless 0.05). Cerebral oxygenation was reduced linearly with CaO2 (r = 0.95, p textless 0.001). Conclusion Collectively, moderate hypoxia induced greater reduction of V̇O2max, peak power output and cerebral oxygenation leading to exercise intolerance in A compared to C. These responses were accompanied by an inability of skeletal muscle to increase O2 utilization at maximal effort in H and by a failure of the cardiovascular system to compensate and counteract convective and diffusion limitations during maximal whole-body exercise in anemic women.