Direct assessment of human placental blood oxygenation can provide valuable information about placental function and, potentially, detect dysfunction. Currently however, no bedside tools exist for non-invasive monitoring of placental oxygenation. Here we report a continuous, non-invasive in vivo method to probe placental oxygen hemodynamics using deep penetrating Frequency Domain Diffuse Optical Spectroscopy (FD-DOS) with concurrent ultrasound (US) imaging. This multi-modal instrument facilitates assessment of placental oxygenation properties from image reconstruction algorithms that integrate anatomical US information about layer morphology with information from optics about functional hemodynamics. Tissue phantom experiments, simulations, and human subject studies validate the approach and demonstrate sensitivity to placental tissue located £ 5 cm below the surface. In a pilot study (n=24), human placental oxygen hemodynamics are measured non-invasively during maternal hyperoxia. Initial results suggest placental response to maternal hyperoxia may serve as a tool to detect placenta-related adverse pregnancy outcome and maternal vascular malperfusion of placenta, weeks before delivery.