Blood flow-restricted resistance exercise improves muscle strength; however, the cardiovascular response is not well understood. This investigation measured local vascular responses, tissue oxygen saturation (StO2), and cardiovascular responses during supine unilateral leg press and heel raise exercise in four conditions: high load with no occlusion cuff, low load with no occlusion cuff, and low load with occlusion cuff pressure set at 1.3 times resting diastolic blood pressure (BFRDBP) or at 1.3 times resting systolic blood pressure (BFRSBP). Subjects (N = 13) (men/women, 5/8, 31.8 ± 12.5 yr, 68.3 ± 12.1 kg, mean ± SD) performed three sets of leg press and heel raise to fatigue with 90-s rest. Artery diameter, velocity time integral, and stroke volume were measured using two-dimensional and Doppler ultrasound at rest and immediately after exercise. HR was monitored using a three-lead ECG. Finger blood pressure was acquired by photoplethysmography. Vastus lateralis StO2 was measured using near-infrared spectroscopy. A repeated-measures ANOVA was used to analyze exercise work and StO2. Multilevel modeling was used to evaluate the effect of exercise condition on vascular and cardiovascular variables. Statistical significance was set a priori at P < 0.05. Artery diameter did not change from baseline during any of the exercise conditions. Blood flow increased after exercise in each condition except BFRSBP. StO2 decreased during exercise and recovered to baseline levels during rest only in low load with no occlusion cuff and high load with no occlusion cuff. HR, stroke volume, and cardiac output (Q˙) responses to exercise were blunted in blood flow-restricted exercise. Blood pressure was elevated during rest intervals in blood flow-restricted exercise. Our results demonstrate that cuff pressure alters the hemodynamic responses to resistance exercise. These findings warrant further evaluations in individuals presenting cardiovascular risk factors.