Intergrading traditional hydrophilic coating with tailored functionalities is critical to enhance its antifouling capabilities. However, designing robust functional antifouling coatings with well-regulated structures to boost its antifouling performance remains a significant challenge. By mimicking the unique structure of shark skin with super-hydrophilic “denticle layer” and low-surface-energy “mucus layer”, for the first time, a facile strategy is presented to hierarchically engineer a triple-defensive antifouling coating, which consists of a hydrophilic mineralized catalytic nanoparticle (NP) layer, overlaid with hydrophobic perfluoro-silane domains (F@NPs), synergistically optimizing its fouling resistance, fouling release, and fouling degradation properties. Force measurements and dynamic simulations demonstrate that molecular-scale incorporation of perfluoroalkyl chains on coating surface significantly reduces foulant adhesion while preserving hydrophilicity, thereby effectively preventing over 98% of oil contamination, protein adsorption, and bio-fluid fouling. Its antifouling properties are further enhanced by the unique catalytic self-cleaning ability, enabling rapid degradation of adsorbed organic compounds and bacteria contact killing. Moreover, F@NPs-coated membrane achieves a water flux over 4200 L m−2 h−1 bar−1 with flux recovery ratio exceeding 95% for separation of oil-in-water emulsions containing bio-foulants. This study presents an innovative strategy for fabricating robust functional coating with superior antifouling performance for environmental engineering applications.