Urea pollution is a growing environmental concern, and its removal via catalytic hydrolysis is challenging due to the resonance-stabilized amide bonds. In nature, this reaction is catalyzed by ureases in many soil bacteria. However, the remedy of this problem with natural enzymes is not feasible as they are easily denatured and require high costs for both preparation and storage. Given this, the development of nanomaterials bearing enzyme-like activity (nanozymes) with advantages such as low production cost, simple storage, and pH/thermal stability has attracted much attention over the past decade. As inspired by the mechanism of urease-catalyzed urea hydrolysis, the co-presence of Lewis acid (LA) and Brønsted acid (BA) sites is imperative to proceed with this reaction. Herein, layered HNb3O8 samples with intrinsic BA sites were adopted for investigation. The layer reduction of this material to few-/single layers can expose Nb sites with various LA strengths depending on the degree of NbO6 distortion. Among the catalysts examined, single-layer HNb3O8 bearing strong LA and BA sites displays the best hydrolytic activity towards acetamide and urea. This sample with high thermal stability was found to outperform urease at temperatures higher than 50 °C. The acidity-activity correlation established in this study is believed to guide the future design of industrial catalysts to remediate urea pollution.