Purposes: We manipulated the inspired oxygen fraction (FiO2) to examine the effects of physiological perturbations on exercise-related sensations and the neural drive of the quadriceps during repeated, brief, maximal cycle sprints. Methods: Nine active males completed a repeated sprint cycle protocol (10 × 4-s maximal sprints with 30 s of passive recovery) in normoxia (NM; FiO2 0.21) and severe normobaric hypoxia (HY; FiO2 0.13). Peak power, quadriceps Root Mean Squared electromyography (RMS EMG), physiological (heart rate, arterial oxygen saturation, blood lactate concentration) and perceptual responses were recorded. Results: The 10 sprints in HY were associated with lower arterial oxygen saturation values compared to NM [80.7 ± 0.9 vs. 95.6 ± 0.6%; P < 0.001; effect size (ES) = 0.98], higher blood lactate values (11.9 ± 0.4 vs. 9.9 ± 0.9 mmol L−1; P = 0.05; ES = 0.36), and greater exercise-related sensations (~36%; P < 0.001; ES > 0.47). Mean power for sprints 1–10 were lower (−13 ± 3%; P = 0.001; ES = 0.79), and sprint decrement was more pronounced in HY compared to NM (21.4 ± 3.7 vs. 13.2 ± 2.7%; P = 0.003). There was a 17% decrease in RMS EMG activity from the first to the last sprint (P < 0.001; ES = 0.65), independent of condition (P = 0.597; ES = 0.04). Conclusions: Despite severe hypoxia exacerbating both physiological and perceptual perturbations, the performance decrement observed during the repeated sprint protocol did not coincide with an accentuated decline in RMS EMG activity. These data suggest that higher-than-normal exercise-related sensations or perceptions coincide with fatigue during repeated sprinting, independent of changes in neural drive, when the task characteristics are known beforehand.