The ability to monitor oxygen delivery in microvasculature plays a vital role in measuring the viability of skin tissue and the probability of recovery. Using currently available clinical imaging tools, it is difficult to observe non-invasive hemodynamic regulation in the peripheral vessels. Here we propose the use of a novel multispectral raster-scanning optoacoustic mesoscopy (RSOM) system for noninvasive clinical monitoring of hemodynamic changes in the skin microvasculature’s oxy- (HbO2) and deoxy-hemoglobin (Hb), total hemoglobin (HbT) and oxygen saturation (rsO2). High resolution images of hemoglobin distribution in the skin microvasculature from six healthy volunteers during venous and arterial occlusion, simulating systemic vascular diseases are presented. During venous occlusion, Hb and HbO2 optoacoustic signals showed an increasing trend with time, followed by a drop in the values after cuff deflation. During arterial occlusion, an increase in Hb value and decrease in HbO2 values was observed, followed by a drop in Hb and jump in HbO2 values after the cuff deflation. A decrease in rsO2 values during both venous and arterial occlusion was observed with an increase in value after occlusion release. Using this proof of concept study, hereby we propose multispectral RSOM as a novel tool to measure high resolution hemodynamic changes in microvasculature for investigating systemic vascular diseases on peripheral tissues and also for monitoring inflammatory skin diseases, and its therapeutic interventions.