Objectives: The purpose of this study was to compare physiological responses to myofascial release (MFR) and passive limb movement (PLM). Design: Nineteen (23 ± 2.6yrs) adults (10 men and 9 women) completed two experiments on separate days: MFR and PLM. Participation included collecting ultrasound images, blood pressure, and heart rate (HR) as well as performing a vascular occlusion test (VOT). The VOT assessed muscle tissue oxygenation (StO2) with near-infrared spectroscopy. Experiments consisted of moving the upper limb to release subtle barriers of resistance in the muscle/fascia (MFR) and passive, assisted range of motion (PLM). Results: There was a significantly (p = 0.012) greater decrease in HR following MFR (-7.3 ± 5.2 BPM) than PLM (-1.3 ± 0.9 BPM). There was an equivalent change in brachial blood flow (-17.3 ± 23.0 vs. -11.9 ± 14.9 mL min-1; p = 0.37) and vascular conductance (-19.3 ± 31.1 vs. -12.4 ± 15.3 mL min-1 mmHg-1; p = 0.38). Microvascular responses differed between the experiments such that MFR exhibited greater area under the curve (AUC, 1503 ± 499.1%∙s-1 vs. 1203 ± 411.1%∙s-1; p = 0.021) and time to maximum StO2 (40.0 ± 8.4s vs. 35.8 ± 7.3s; p = 0.009). Conclusions: As evidenced by HR, MFR induced greater parasympathetic activity than PLM. The greater AUC and time to StO2max following MFR suggested a spillover effect to induce prolonged hyper-saturation. These results may be of interest to those investigating possible MFR-related rehabilitative benefits.