The novel poly(dimethyl siloxane-urethane)/Pluronic hydrogel was fabricated to develop a new ophthalmically compatible material. In this study, the soft segment consists of poly(dimethylsiloxane) dialkanol having hydroxyethyl propoxy end groups and hard segment consists of isophorone diisocyanate (IPDI). The poly(ethylene glycol) methacrylate (PEGMA) was added as the chain-extender to form UV-curable silicone marcomer. Finally, the semi-interpenetrating network (semi-IPN) hydrogel was achieved by reacting with silicone marcomer and Pluronic F127 triblock copolymer under UV-photopolymerization (mSi-PU/F127). It was found that the increase in Pluronic F127 content led to decreased water contact angle and increased the water content of silicone hydrogels. Elastic modulus also decreased with Pluronic F127 content, while surface roughness did not significantly differ from silicone controls. The Pluronic F127 content reached 4%, the apparent protein adsorption amount decreased about 60% in comparison with that of mSi-PU control. It indicated that the mSi-PU/F127 hydrogel membrane had an excellent ability to resist protein adsorption. Additionally, the oxygen permeability (Dk) would decrease 24%, as compared with mSi-PU control. Furthermore, these hydrogel membranes were regarded as non-cytotoxic through in vitro L929 fibroblasts proliferation assay. Overall results demonstrated that the mSi-PU/F127 semi-IPN hydrogel provided silicone hydrogel materials not only having relatively high oxygen permeability and a relatively low modulus, but also enhancing hydrophilicity and anti-protein adsorption.