The aim of this study was to assess the effects of oxygen availability (normoxia vs. hypoxia), muscle mass and exercise type on pulse oxygen saturation, and quadriceps muscle oxygenation during repeated sprint exercises. Sixteen healthy participants completed 5 mathematical equation 12 s sprints (21 s rest). This sprint-like exercise was performed under two environmental conditions (normoxia: FiO2 = 21%; systemic hypoxia: FiO2 = 13%) and for three exercise modalities: unilateral knee extensions (KE) involving the right leg extensors (UNI), bilateral KE involving both legs extensors (BIL), and bilateral leg cycling (CYC). Measurements included power output, pulse oxygen saturation (SpO2), and vastus lateralis oxygenation (delta in tissue saturation index; ΔTSI). In hypoxia, a similar minimal SpO2 was reported in UNI and BIL but SpO2 was lower in CYC (p = 0.047 and p = 0.021). ΔTSI during sprints and recoveries were similar in UNI and BIL but greater in CYC (p textless 0.001) and in normoxia compared to hypoxia (main condition effect; p = 0.002). The power output was lower during KE exercises than during cycling, and no effect of hypoxia has been reported. The main results of this study indicate that unilateral and bilateral KE at high intensity induce comparable pulse and local muscular desaturation in hypoxia, and that these alterations are exacerbated during cycling.