In this work, we present a green synthesis approach for obtaining silver nanoparticles (AgNPs) using peel extract from the autochthonous Mollar de Elche pomegranate variety. The process was optimized using a Box–Behnken design (BBD) implemented in Python to evaluate the influence of silver nitrate concentration, extract concentration and temperature. Pomegranate bioactive compounds, especially punicalagin, acted as natural reducing and stabilizing agents. BBD enabled the identification of key factor interactions while reducing the number of required experiments. The optimal synthesis conditions predicted by the model were experimentally validated, showing strong agreement with theoretical values. The resulting AgNPs were characterized by UV–Vis spectroscopy, FTIR, XRD, and field-emission microscopy, confirming their successful formation and stability. These AgNPs demonstrated substantial antibacterial activity against Escherichia coli and Staphylococcus aureus. Furthermore, the AgNPs were incorporated into nanofibrous scaffolds as a proof of concept for potential biomedical applications, where their antibacterial activity was partially retained postincorporation. This study highlights the potential of pomegranate extract as a sustainable medium for AgNP synthesis with promising antibacterial applications and the ability of the BBD as a useful tool for efficient optimization of multivariable processes, including the synthesis of nanomaterials.