Extreme prematurity carries a high burden of morbidity and mortality. The artificial placenta is an emerging therapy that has the potential to improve outcomes in these patients. However, current devices in development are limited by inadequate hemocompatibility, a major barrier to the translation of the artificial placenta into humans. Here, we present a novel microfluidic oxygenator that is comprised of a stacked array of semiconductor silicon membranes and operates with minimal anticoagulation (activated clotting time = 120–180 s). We describe the design, construction, and testing of two generations of prototypes. Our Generation 2 Device had an oxygen transfer of 1.51 ± 0.25 volume % (mean ± standard error). Computational fluid dynamics (CFD) modeling demonstrated favorable blood flow properties, including laminar flow, no stasis or recirculation, and optimal wall shear stress. In vivo testing in a 6 hour neonatal swine model showed that the silicon membrane oxygenator could operate with low-dose anticoagulation with minimal clot formation. Furthermore, the oxygenator had no significant effect on markers of animal health, including inflammation (white blood cell count), coagulation (platelet count, prothrombin time), or hemolysis (hematocrit, plasma free hemoglobin). This study represents a key advance toward developing an anticoagulation-free oxygenator and ultimately bringing artificial placenta technology to patients.