In this study, the ultrasonic extraction method was employed to obtain extracts with high total phenolic matter (TFM) content and antioxidant activity (DPPH) from ginger powders for use in food applications. For water extraction, process variables such as solvent ratio (1-5%), ultrasonication (US) temperature (25-55 °C), and US time (5-15 min) that maximize TFM and DPPH responses were tested using a Box-Behnken design. The optimum conditions were determined by Design Expert software using the response surface methodology (RSM). In addition, the statistical effects of the extraction model and model parameters were determined through analysis of variance (ANOVA). In this work, the process factors that maximized TFM (106.45 mg GAE/100 mL extract) and DPPH (52.23%) responses were determined as 5% solvent ratio, 26 °C US temperature and 5 min US time. ANOVA analysis revealed that the effect of the solvent ratio on both responses was significant (p < 0.05). Moreover, the solvent ratio variable, with the highest F and the lowest p-value, was the most important factor affecting the extraction process. According to the results, RSM can be used to optimize the water extraction process of active ingredients from plant rhizomes with high bioactive content using ultrasound application.