Liver diseases pose a significant global health burden, with limited therapeutic options for chronic cases. Zinc oxide (ZnO) nanomaterials have emerged as promising candidates for hepatoprotection due to their antioxidant, anti-inflammatory, and regenerative properties. However, their potential remains hampered by insufficient drug loading and controlled release. The current study explores the intercalation of Naproxen (Nx), a potent anti-inflammatory and analgesic drug, within ZnO stacked nanosheets (SNSs) to address these limitations. Herein, an easy and solution-based synthesis of novel Nx intercalated ZnO SNSs was established. The obtained Nx intercalated ZnO SNSs were encapsulated with poly(vinyl acetate) (PVA) to make them biocompatible. The synthesized biocomposite was characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), and Fourier transform infrared spectroscopy (FTIR), which confirm the successful synthesis and intercalation of Nx within the ZnO SNSs. The obtained outcomes showed that the configuration of ZnO nanosheets was altered when Nx was introduced, resulting in a more organized stacking pattern. An in vivo investigation of mice liver cells unveiled that the Nx intercalated ZnO SNss had increased hepatoprotective properties. The study’s results provide valuable insights into using Nx intercalated ZnO SNss for targeted drug delivery and improved treatment effectiveness, particularly for liver-related illnesses.