Purpose The aims of this study were to compare cerebral hemodynamics and maximal oxygen uptake (VO2peak) in patients with end-stage renal disease (ESRD) vs. age-matched healthy controls during maximal exercise. Methods Twelve patients with ESRD and twelve healthy adults (CTR group) performed exhaustive incremental exercise test. Throughout the exercise test, near-infrared spectroscopy allowed the investigation of changes in oxyhemoglobin (∆O2Hb), deoxyhemoglobin (∆HHb), and total hemoglobin (∆THb) in the prefrontal cortex. Results Compared to CTR, VO2peak was significantly lower in ESRD group (P < 0.05). Increase in ∆THb (i.e., cerebral blood volume) was significantly blunted in ESRD (P < 0.05). ESRD patients also had impaired changes in cerebral ∆HHb and ∆O2Hb during high intensity of exercise (P < 0.05). Finally, no significant correlation was observed between VO2peak and changes in cerebral hemodynamics parameters in both groups (All P > 0.05). Conclusion Maximal exercise highlights subtle disorders of both hemodynamics and neuronal oxygenation in the prefrontal cortex in patients with ESRD. This may contribute to both impaired cognitive function and reduced exercise tolerance throughout the progression of the disease.