The artificial lung has provided life‐saving support for pulmonary disease patients and recently afforded patients with severe cases of COVID‐19 better prognostic outcomes. While it addresses a critical medical need, reducing the risk of clotting inside the device remains challenging. Herein, a two‐step surface coating process of the lung circuit using Zwitterionic polysulfobetaine methacrylate is evaluated for its nonspecific protein antifouling activity. It is hypothesized that similarly applied coatings on materials integrated (IT) or nonintegrated (NIT) into the circuit will yield similar antifouling activity. The effects of human plasma preconditioned with nitric oxide‐loaded liposome on platelet (plt) fouling are also evaluated. Fibrinogen antifouling activities in coated fibers are similar in the IT and NIT groups. It however decreases in coated polycarbonate (PC) in the IT group. Also, plt antifouling activity in coated fibers is similar in the IT and NIT groups and is lower in coated PC and Tygon in the IT group compared to the NIT group. Coating process optimization in the IT lung circuit may help address difference in the coating appearance of outer and inner fiber bundle fibers, and the NO‐liposome significantly reduces (86%) plt fouling on fibers indicating its potential use for blood anticoagulation.