Polymer brushes, which can achieve lubrication and anti-adhesion properties, have become an important method for surface modification of medical devices. However, the existing polymer brushes are complicated to prepare or have harsh reaction conditions. Thus, this study develops a surface wettability modulation-based rapid fabrication approach for zwitterionic polymer brushes using a single photoinitiator. This strategy modulates surface wettability by synthesizing a waterborne polyurethane /poly(ethylene glycol) diacrylate (WPU/PEGDA) hydrogel layer, while its porous structure facilitates subsurface-initiated growth of sulfobetaine methacrylate (SBMA) polymer brushes, synergistically enhancing grafting efficiency (40 min) and stability (coating loss <7.5 μg/cm 2 post-7 h sonication). The resultant coatings exhibit ultralow friction (< 0.005) without wear during prolonged use. Notably, through combined macroscopic friction tests and molecular dynamics simulations, hydration lubrication theory was extended by demonstrating load-dependent hydration layer thickness regulation and its correlation with friction behavior in SBMA brush systems. The polymer brush coating also exhibits excellent anti-protein/cell adhesion and thrombosis prevention. In conclusion, this wetting gradient-matched fabrication strategy enables the rapid preparation of polymer brushes for medical devices with robust lubrication, anti-adhesion, and antibacterial properties.