Nitric oxide (NO) plays a significant role in controlling the physiology and pathophysiology of the body, including the endothelial antiplatelet function and therefore, antithrombogenic property of the blood vessels. This property of NO can be exploited to prevent thrombus formation on artificial surfaces like extracorporeal membrane oxygenators, which when come into contact with blood lead to protein adsorption and thereby platelet activation causing thrombus formation. However, NO is extremely reactive and has a very short biological half‐life in blood, so only endogenous generation of NO from the blood contacting material can result into a stable and kinetically controllable local delivery of NO. In this regards, highly hydrophilic bioactive nanogels are presented which can endogenously generate NO in blood plasma from endogenous NO‐donors thereby maintaining a physiological NO flux. It is shown that NO releasing nanogels could initiate cGMP‐dependent protein kinase signaling followed by phosphorylation of vasodilator‐stimulated phosphoprotein in platelets. This prevents platelet activation and aggregation even in presence of highly potent platelet activators like thrombin, adenosine 5′‐diphosphate, and U46619 (thromboxane A2 mimetic). Highly hydrophilic bioactive nanogels are designed to endogeneously generate nitric oxide in blood plasma from endogenous nitric oxide‐donors to maintain a physiological nitic oxide flux. The nanogels could initiated cyclic guanosine monophosphate‐dependent protein kinase signaling followed by phosphorylation of vasodilator‐stimulated phosphoproteinin platelets. This prevented platelet activation and aggregation even in presence of highly potent platelet activators.