Hydrotalcite‐ zinc‐silver nanoparticles (HT‐Zn‐AgNPs) have been applied in many different fields such as antibacterial, cosmetic, and so on. NaBH4 has often been used as a chemical‐reducing agent to decorate silver on the HT‐Zn surface. However, it wields an adverse influence on the environment. As a result, using piper betle leaf extract (PBE) is considered a potential candidate because of its friendly environment. This study focused on optimizing the synthesis of AgNPs on HT‐Zn using a PBE‐reducing agent by utilizing the response surface methodology and Box–Behnken design. Scanning electron microscopy and transmission electron microscopy images showed that after doping Zn on the HT surface, the structure of HT did not change too much while after decorating AgNPs on hydrotalcite‐zinc (HT‐Zn), the AgNPs dispersed on HT‐Zn surface with spherical shape. The ultraviolet–visible (UV–vis) spectra analysis indicated the appearance of AgNPs at a peak of about 480 nm, corresponding to the surface plasmonic effect of AgNPs. Besides, the successful synthesis of HT‐Zn and HT‐Zn‐AgNPs was also proved through the analysis results of X‐ray diffraction, infrared, and atomic absorbance spectroscopy (AAS). The optimal conditions were found including a reaction temperature of 30 °C, reaction time of 6.9 h, and volume of PBE of 1.06 mL (for 0.02 g AgNO3). The experimental yield for synthesizing HT‐Zn‐AgNPs reached 62.12%, which is close to the predict yield of 62.91%. Moreover, the study also indicated the antibacterial ability of HT‐Zn‐AgNPs with Escherichia coli, Pseudomonas stutzeri B27, and antibiotic‐resistant E. coli bacteria. In summary, the HT‐Zn hybrid AgNPs using PBE as a reducing agent for the reduction of AgNPs is very promising for antibacterial additives.