Purpose: This study aimed to determine the effects of hypoxia and/or blood flow restriction (BFR) on an arm-cycling repeated sprint ability test (aRSA) and its impact on elbow flexor neuromuscular function. Methods: Fourteen volunteers performed an aRSA (10 s sprint/20 s recovery) to exhaustion in four randomized conditions: normoxia (NOR), normoxia plus BFR (NBFR), hypoxia (FiO2 = 0.13, HYP) and hypoxia plus BFR (HBFR). Maximal voluntary contraction (MVC), resting twitch force (Db10), and electromyographic responses from the elbow flexors [biceps brachii (BB)] to electrical and transcranial magnetic stimulation were obtained to assess neuromuscular function. Main effects of hypoxia, BFR, and interaction were analyzed on delta values from pre- to post-exercise. Results: BFR and hypoxia decreased the number of sprints during aRSA with no significant cumulative effect (NOR 16 ± 8; NBFR 12 ± 4; HYP 10 ± 3 and HBFR 8 ± 3; P < 0.01). MVC decrease from pre- to post-exercise was comparable whatever the condition. M-wave amplitude (− 9.4 ± 1.9% vs. + 0.8 ± 2.0%, P < 0.01) and Db10 force (− 41.8 ± 4.7% vs. − 27.9 ± 4.5%, P < 0.01) were more altered after aRSA with BFR compared to without BFR. The exercise-induced increase in corticospinal excitability was significantly lower in hypoxic vs. normoxic conditions (e.g., BB motor evoked potential at 75% of MVC: − 2.4 ± 4.2% vs. + 16.0 ± 5.9%, respectively, P = 0.03). Conclusion: BFR and hypoxia led to comparable aRSA performance impairments but with distinct fatigue etiology. BFR impaired the muscle excitation–contraction coupling whereas hypoxia predominantly affected corticospinal excitability indicating incapacity of the corticospinal pathway to adapt to fatigue as in normoxia.