Introduction: Exercise with blood flow restriction (BFR) is emerging as an effective modality for improving muscular function in clinical and athletic populations. Selection of cuff pressure is critical because it should maximize metabolic stress without completely occluding blood flow or compromising user safety. It is unknown how cuff pressures determined at rest influence blood flow hemodynamics during exercise. Purpose: We evaluated changes in blood flow and tissue perfusion before, during, and after exercise with BFR. Methods: Ten males performed rhythmic handgrip exercise (30 contractions, 30% MVC) at 0%, 60%, 80%, 100%, and 120% of limb occlusion pressure (LOP). Brachial artery blood flow and tissue saturation were assessed using Doppler ultrasound and near-infrared spectroscopy, respectively. Results: At rest blood flow generally decreased with increased pressure (0% > 60% ≈ 80% > 100% ≈ 120% LOP). During 60% and 80% LOP conditions, blood flow increased during exercise from rest and decreased after exercise (all P < 0.05). Compared to 0% LOP, relative blood flow at 60% and 80% LOP decreased by 22–47% at rest, 22–48% during exercise, and 52–71% after exercise (all P < 0.05). Increased LOP decreased tissue saturation during exercise with BFR (P < 0.05). Heart rate, mean arterial pressure, and cardiac output did not differ across LOP. Conclusion: At pressures below LOP the cardiovascular system overcame the external pressure and increased blood flow to exercising muscles. Relative reductions in blood flow at rest were similar to those during exercise. Thus, the relative occlusion measured at rest approximated the degree of occlusion during exercise. Moderate cuff pressures increased metabolic stress without completely occluding blood flow.