Purpose: We aimed to identify a blood flow restriction (BFR) endurance exercise protocol that would both maximize cardiopulmonary and metabolic strain, and minimize the perception of effort. Methods: Twelve healthy males (23 ± 2 years, 75 ± 7 kg) performed five different exercise protocols in randomized order: HI, high-intensity exercise starting at 105% of the incremental peak power (Ppeak); I-BFR30, intermittent BFR at 30% Ppeak; C-BFR30, continuous BFR at 30% Ppeak; CON30, control exercise without BFR at 30% Ppeak; I-BFR0, intermittent BFR during unloaded exercise. Cardiopulmonary, gastrocnemius oxygenation (StO2), capillary lactate ([La]), and perceived exertion (RPE) were measured. Results: V̇O2, ventilation (V̇E), heart rate (HR), [La] and RPE were greater in HI than all other protocols. However, muscle StO2 was not different between HI (set1—57.8 ± 5.8; set2—58.1 ± 7.2%) and I-BRF30 (set1—59.4 ± 4.1; set2—60.5 ± 6.6%, p < 0.05). While physiologic responses were mostly similar between I-BFR30 and C-BFR30, [La] was greater in I-BFR30 (4.2 ± 1.1 vs. 2.6 ± 1.1 mmol L−1, p = 0.014) and RPE was less (5.6 ± 2.1 and 7.4 ± 2.6; p = 0.014). I-BFR30 showed similar reduced muscle StO2 compared with HI, and increased blood lactate compared to C-BFR30 exercise. Conclusion: Therefore, this study demonstrate that endurance cycling with intermittent BFR promotes muscle deoxygenation and metabolic strain, which may translate into increased endurance training adaptations while minimizing power output and RPE.