Green synthesis of silver nanoparticles (AgNPs) involves a reduction reaction of a metal salt solution mixed with a plant extract. The reaction yield can be controlled using several independent factors, such as extract and metal concentration, temperature, and incubation time. AgNPs from Origanum vulgare (oregano) were synthesized in the past. However, no investigations were performed on the combined effects of independent factors that affect the synthesis. In this work, silver nitrate, oregano extract, and sodium hydroxide (NaOH) concentrations were chosen as the independent factors, and full factorial design under Response Surface Methodology was employed. UV–Vis absorbance spectroscopy, X-ray Powder Diffraction (XRD), and Fourier Transform Infrared Spectroscopy (FTIR) were used to characterize the nanoparticles. A Voigt function was fitted on the measured UV–Vis spectra. The fitting parameters of the Voigt function, peak wavelength, area, and Full Width at Half Maximum, were used as the responses. A quadratic model was fitted for the peak wavelength and area. The NaOH concentration proved to be the dominant factor in nanoparticle synthesis. UV–Vis absorbance showed a characteristic plasmon resonance of AgNPs at 409 nm. XRD verified the crystallinity of the nanoparticles and FTIR identified the ligands involved.