This study examined the influence of muscle deoxygenation and reoxygenation on repeated-sprint performance via manipulation of O2 delivery. Fourteen team-sport players performed 10 10-s sprints (30-s recovery) under normoxic (NM: FIO2 0.21) and acute hypoxic (HY: FIO2 0.13) conditions in a randomized, single-blind fashion and crossover design. Mechanical work was calculated and arterial O2 saturation (SpO2) was estimated via pulse oximetry for every sprint. Muscle deoxyhemoglobin concentration ([HHb]) was monitored continuously by near-infrared spectroscopy. Differences between NM and HY data were analyzed for practical significance using magnitude-based inferences. HY reduced SpO2 (–10.7 ± 1.9%, with chances to observe a higher/similar/lower value in HY of 0/0/100%) and mechanical work (–8.2 ± 2.1%; 0/0/100%). Muscle deoxygenation increased during sprints in both environments, but was almost certainly higher in HY (12.5 ± 3.1%, 100/0/0%). Between-sprint muscle reoxygenation was likely more attenuated in HY (–11.1 ± 11.9%; 2/7/91%). The impairment in mechanical work in HY was very largely correlated with HY-induced attenuation in muscle reoxygenation (r = 0.78, 90% confidence limits: 0.49; 0.91). Repeated-sprint performance is related, in part, to muscle reoxygenation capacity during recovery periods. These results extend previous findings that muscle O2 availability is important for prolonged repeated-sprint performance, in particular when the exercise is taken in hypoxia.