Objectives: The hydrolysis and enzymolysis of ester groups in dental resins weaken restorative materials and reduce their service lives. Current methods for evaluating biostability of dental resins take long time (from weeks to months) and include expensive labor and enzymes needed for testing. The objective of this study was to develop a new method using nano-surface topography to accelerate the assessment of polymer degradation in biologically relevant environment. Methods: Ultra-flat resin films of urethane dimethacrylate and triethylene glycol dimethacrylate copolymers (equimolar ratio) were produced by employing nano-imprint lithograph. Gold-covered and bare-resin areas were generated simultaneously by mask-guided metal evaporation resulting in protected and degradable areas, respectively, on one sample. The step-height between gold and resin surfaces was 17 nm. These areas were challenged by a salivary enzyme and/or control medium for 4 h to 72 h. After challenges, step-height changes were determined by atomic force microscopy (tapping mode) to quantify the extent of degradation. Results: Significant enzymatic degradation was detected as early as 4 h after challenges. The step-height change caused by enzymatic hydrolysis was 8 nm for 4h, and the value increased to 113 nm after 72h. Leaching effect of control sample without adding enzyme was also investigated. The rates for both leaching and degradation decreased after 24 h. Conclusions: Nano-surface topography was proven effective in quantifying the degradation of ester-containing dental resins. It significantly saves labor, time and cost. This new method has strong potential as an advanced tool for material evaluation and development.