Antithrombotic coating material is indispensable for the production of blood-contacting medical devices. Physical coatings of inexpensive synthetic polymers are desirable to reduce medical expenses and provide patients with an opportunity to receive medical care. Poly(2-methoxyethyl acrylate) (PMEA) homopolymers are widely diffused coating materials that almost meet these requirements. However, the PMEA homopolymer coating has room for improvement because its poor coating properties cause dewetting, thus limiting the available substrates. Herein, we fabricated an inorganic/organic hybrid material using silsesquioxane (SQ) and poly(2-methoxyethyl acrylate) (PMEA) called the SQ/PMEA hybrid to overcome the limitations of existing PMEA homopolymer coatings. The SQ/PMEA hybrid was successfully synthesized by thiol-initiated radical polymerization of 2-methoxyethyl acrylate (MEA) from thiol group-containing random-type silsesquioxane (SQ-SH) utilizing 2,2′-azobis(isobutyronitrile) as a thermal initiator. This polymerization strategy readily afforded the required hybrid with various Si contents by merely changing the feed composition of the monomer and SQ-SH without a complicated procedure. The SQ/PMEA hybrid showed the formation of intermediate water essential for biocompatibility in any polymer composition. By optimizing the Si content, the hybrid formed a smooth and stable coating layer on surfaces of polymers, ceramics, and metals compared with the PMEA homopolymer even under wet conditions and significantly suppressed human platelet adhesion. In addition, the hybrid coating not only exhibited antithrombotic properties but also drastically promoted the adhesion and extension of human umbilical vein endothelial cells (HUVECs). These characteristics of the hybrid material are attractive for the surface treatment of blood-contacting devices used for a long time, including extracorporeal membrane oxygenation (ECMO) devices, blood vessels, and stents. This strategy has potential in the advancement of the biomedical fields such as tissue engineering, regenerative medicine, and minimally invasive medicine.