This study aimed to elucidate whether muscle blood flow restriction during maximal exercise is associated with alterations in hemodynamics, cerebral oxygenation, cerebral activation, and deterioration of exercise performance in male participants. Thirteen healthy males, cyclists (age 33 ± 2 yrs., body mass: 78.6 ± 2.5 kg, and body mass index: 25.57 ± 0.91 kg·m−1), performed a maximal incremental exercise test on a bicycle ergometer in two experimental conditions: (a) with muscle blood flow restriction through the application of thigh cuffs inflated at 120 mmHg (with cuffs, WC) and (b) without restriction (no cuffs, NC). Exercise performance significantly deteriorated with muscle blood flow restriction, as evidenced by the reductions in V˙O2max (−17 ± 2%, p textless 0.001), peak power output (−28 ± 2%, p textless 0.001), and time to exhaustion (−28 ± 2%, p textless 0.001). Muscle oxygenated hemoglobin (Δ[O2Hb]) during exercise declined more in the NC condition (p textless 0.01); however, at exhaustion, the magnitude of muscle oxygenation and muscle deoxygenation were similar between conditions (p textgreater 0.05). At maximal effort, lower cerebral deoxygenated hemoglobin (Δ[HHb]) and cerebral total hemoglobin (Δ[THb]) were observed in WC (p textless 0.001), accompanied by a lower cardiac output, heart rate, and stroke volume vs. the NC condition (p textless 0.01), whereas systolic blood pressure, rating of perceived exertion, and cerebral activation (as assessed by electroencephalography (EEG) activity) were similar (p textgreater 0.05) between conditions at task failure, despite marked differences in exercise duration, maximal aerobic power output, and V˙O2max. In conclusion, in trained cyclists, muscle blood flow restriction during an incremental cycling exercise test significantly limited exercise performance. Exercise intolerance with muscle blood flow restriction was mainly associated with attenuated cardiac responses, despite cerebral activation reaching similar maximal levels as without muscle blood flow restriction.