Despite extensive efforts toward developing anti-biofilm materials, efficient prevention of biofilm formation remains challenging. Diverse polymeric materials with bactericidal or antifouling properties have strong potential as efficient antibiofilm materials. However, approaches based on a single strategy using either bactericidal polymers, antifouling coatings, or nano-patterning of polymers have shown limited performance in the prevention of biofilm formation. This study presents a lipid-hydrogel-nanotopography hybrid that has highly efficient biofilm-resistant properties. The hybrid material consists of nanostructured antifouling, biocompatible polyethylene glycol (PEG)-based polymer covered with a membrane-mimicking, antifouling, biocompatible zwitterionic polymer of 2-methacryloryloxyethyl phosphorylcholine (MPC). Surface chemistry of the polymeric hybrid is analyzed with attenuated total reflectance-fourier transform infrared (ATR-FTIR) spectroscopy and x-ray photoelectron spectroscopy (XPS). Based on the unique heterogeneous chemical compositions, the lipid-hydrogel-nanostructure hybrid exhibits superior dual functionalities of antifouling and bactericidal activities against gram-negative and -positive bacteria, compared with those of surfaces composed of single type of polymer.