Extensive efforts have been devoted toward developing antibiofilm materials that can efficiently suppress bacterial attachment and subsequent biofilm formation. However, many of the previous approaches are based on non-biocompatible, non-degradable, and environmentally harmful synthetic materials. Herein, we report an efficient and sustainable biofilm-resistant material that is made of a biocompatible, biodegradable, and naturally abundant cellulose derivate biopolymer. The biofilm-resistant material is made of cellulose acetate (CA) and possesses precisely defined nanoscale needle-like architectures on its surface. The CA nanoneedle array is further coated with a cell-membrane mimicking monomer of 2-methacryloryloxyethyl phosphorylcholine (MPC). Based on the synergetic integration of the bio- and environment-friendly polymers of CA and MPC into nanoscale topography, the nanostructured CA not only effectively prevents bacterial attachment but also simultaneously exhibits strong bactericidal effects against both gram-positive and gram-negative bacteria. This natural cellulose derivative-based nanostructured material has strong potential as a biocompatible, and eco-friendly antibiofilm material for versatile uses in biomedical and industrial applications.