Sargassum horneri (SH) is a promising marine bioresource for producing bioactive compounds. Recently, the biological functions (including anti-inflammatory, antioxidant, and anticancer activities) of SH extracts have been revealed; however, efficient extraction processes to produce bioactive molecules (such as tannin and phenol) have not been carefully designed. In this study, the ultrasound-assisted extraction process was optimized based on the response surface methodology (RSM) to efficiently produce tannin and phenol from SH. Significant RSM models (p < 0.05) for predicting tannin and phenol yields were developed, and prethanol A concentration, temperature, and solid loading were significantly affected by tannin or phenol yield (p < 0.05). Following numerical optimization, the tannin and phenol yields achieved 14.59 and 13.83 mg/g biomass, respectively, under optimal conditions (39.1% solvent, 61.9 °C, 52.0 g/L solid loading, and 49.0% amplitude), similar to the model-predicted values (12.95 and 13.37 mg/g, respectively). Then, time profiling under optimal conditions determined the optimal time as 10.0 min, resulting in the highest yield (15.88 mg tannin and 14.55 mg phenol/g). The extracts showed antioxidant activity (IC₅₀: 79.86 μg/mL) comparable to that of ascorbic acid (vitamin C). It was found to be particularly non-toxic, raising its potential as a functional ingredient in food or cosmetics.