The aim was to evaluate changes in peripheral and cerebral oxygenation, cardiorespiratory, and performance differences, as well as neuromuscular fatigue across multiple levels of blood flow restriction (BFR) during a repeated cycling sprint test to exhaustion (RST). Participants performed three RST (10-sec maximal sprints with 20-sec recovery until exhaustion) with measurements of power output and V̇O2peak as well as oxygenation (near-infrared spectroscopy) of the vastus lateralis and prefrontal cortex. Neuromuscular fatigue was assessed by femoral nerve stimulation to evoke the vastus lateralis. Tests were conducted with proximal lower limb bilateral vascular occlusion at 0%, 45%, and 60% of resting pulse elimination pressure. Total work decreased with BFR (52.5 ± 22.9% at 45%, 68.6 ± 32.6% at 60%, P < 0.01 compared with 0%) as V̇O2peak (12.6 ± 9.3% at 45%, 18.2 ± 7.2% at 60%, compared with 0%, P < 0.01). Decreased changes in muscle deoxyhemoglobin (∆[HHb]) during sprints were demonstrated at 60% compared to 0% (P < 0.001). Changes in total hemoglobin concentrations (∆[tHb]) increased at both 45% and 60% compared with 0% (P < 0.001). Cerebral ∆[tHb] increased toward exhaustion (P < 0.05). Maximal voluntary contraction (MVC), voluntary activation level (VAL), and root mean square (RMS)/M-wave ratio decreased at 60% compared with 0% (P < 0.001, all). MVC and VAL decreased between 45% and 60% (P < 0.05, both). The application of BFR during RST induced greater changes in tissue perfusion (via blood volume, ∆[tHb]) suggesting a possible stimulus for vascular blood flow regulation. Additionally, high-intensity sprint exercise with partial ischemia may challenge cerebral blood flow regulation and influence local fatigue development due to protection of cerebral function.