Real-time, quantitative biosensing within extracorporeal perfusion (ECP) and extracorporeal membrane oxygenation (ECMO) systems is key to advancing this life-support technology beyond the hospital setting to emergency care. Measuring and monitoring  concentration in blood is particularly important but is challenged by fouling of the sensor. Here we report a novel hydrogel nanocomposite coating, composed of polysulfobetaine, polyethylene glycol, and titanium dioxide nanoparticles, for a metalloporphyrin-based oxygen sensor. The hydrogel nanocomposite exhibits minimal cytotoxicity and hemolytic effects (< 5%), as well as non-adhesive and non-coagulant properties in contact with lung endothelial cells and human plasma, ensuring its compatibility with blood-contacting applications. The incorporation of titanium dioxide nanoparticles provides a white, light-scattering surface to improve sensor signal reflection, enhances the hydrogel’s mechanical strength (storage modulus > 1000 Pa), and maintains a pore area on the order of μm² to facilitate efficient fluid and gas diffusion to the oxygen sensing film. Notably, the hydrogel nanocomposite enables rapid, accurate (within 2 mmHg of the analytical reference), and continuous monitoring of oxygen partial pressures () in PBS and blood for over 90 minutes within a miniaturized flow cell integrated in an extracorporeal perfusion-mimicking system. To our knowledge, this is the first report of a blood-compatible biomaterial that enables real-time  monitoring in a lightweight, compact sensor, suitable for integration into ECP and ECMO circuits.