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Background: Extracorporeal organ assist devices provide lifesaving functions for acutely and chronically ill patients suffering from respiratory and renal failure, but their availability and use is severely limited by an extremely high level of operational complexity. While current hollow fiber‐based devices provide high‐efficiency blood gas transfer and waste removal in extracorporeal membrane oxygenation (ECMO) and hemodialysis, respectively, their impact on blood health is often highly deleterious and difficult to control. Further challenges are encountered when integrating multiple organ support functions, as is often required when ECMO and ultrafiltration (UF) are combined to deal with fluid overload in critically ill patients, necessitating an unwieldy circuit containing two separate cartridges. Methods: We report the first laboratory demonstration of simultaneous blood gas oxygenation and fluid removal in single microfluidic circuit, an achievement enabled by the microchannel‐based blood flow configuration of the device. Porcine blood is flowed through a stack of two microfluidic layers, one with a non‐porous, gas‐permeable silicone membrane separating blood and oxygen chambers, and the other containing a porous dialysis membrane separating blood and filtrate compartments. Results: High levels of oxygen transfer are measured across the oxygenator, while tunable rates of fluid removal, governed by the transmembrane pressure (TMP), are achieved across the UF layer. Key parameters including the blood flow rate, TMP and hematocrit are monitored and compared with computationally predicted performance metrics. Conclusions: These results represent a model demonstration of a potential future clinical therapy where respiratory support and fluid removal are both realized through a single monolithic cartridge. [ABSTRACT FROM AUTHOR]