Abstract Purpose To determine the effects of load carriage in normoxia and normobaric hypoxia on ventilatory responses, hemodynamics, tissue oxygenation, and metabolism. Methods Healthy males (n = 12) completed 3 randomly ordered baseline graded exercise tests in the following conditions: (1) unloaded normoxic (U: F I O 2 = 20.93%), (2) loaded (~ 30 kg) normoxic (LN), and (3) loaded hypoxic simulating ~ 3650 m (LH: F I O 2 = ~ 13%). Thereafter, experimental exercise trials were completed in quasi-randomized order (i.e., U completed first) consisting of 3 × 10 min of walking (separated by 5 min seated rest) with stages matched with the U condition (in ascending order) for relative intensity, absolute oxygen consumption ([VO 2 ]; 1.7 L min −1 ), and walking speed (1.45 ± 0.15 m s −1 ). Results Load carriage increased perceived exertion and reduced VO 2max (LN: − 7%; LH: − 32%; p textless 0.05). At matched VO 2 , stroke volume and tidal volume were reduced and maintained with LN and LH vs. U, respectively ( p textless 0.05). Increases in cardiac output and minute ventilation at matched VO 2 (with LH) and speed (with LN and LH), were primarily accomplished via increases in heart rate and breathing frequency ( p textless 0.05). Cerebral oxygenated hemoglobin (O 2 HHb) was increased at all intensities with LN, but deoxygenated hemoglobin and total hemoglobin were increased with LH ( p textless 0.05). Muscle oxygen kinetics and substrate utilization were similar between LN and U, but LH increased CHO dependence and reduced muscle O 2 HHb at matched speed ( p textless 0.05). Conclusion Load carriage reduces cardiorespiratory efficiency and increases physiological strain, particularly in hypoxic environments. Potential load carriage-induced alterations in cerebral blood flow may increase the risk for altitude illnesses and requires further study.