In order to improve development and utilization value of guava, the extraction of phenolic compounds from guava seed and its antioxidant activity were evaluated. Based on the single factor experiment, an optimization of 3-factor and 3-level by response surface methodology was designed and carried out to construct regression model and obtain optimal condition of ultrasonic power, ethanol concentration and water to raw material ratio. Then capacities of scavenging hydroxyl free radical and superoxide anion free radical were used to evaluate antioxidant capacity of phenolic compounds extraction. Results showed that the optimal technological condition was determined as ultrasonic power of 345 W, ethanol concentration of 70%, and water to raw material ratio of 22 mL/g. Under these conditions, the experimental yield of phenolic compounds was 2.302 mg/g, which agreed closely with the predicted value (2.340 mg/g). At the same time the study of antioxidant activity exhibited stronger antioxidant activity of phenolic compounds in guava seed than ascorbic acid. Its maximal scavenging rates for hydroxyl free radical and superoxide anion free radical were 62.38% and 80.23%, and the values of IC50 were 154 µg/mL and 552 µg/mL, respectively. Hence the phenolic compounds in guava seed is abundant and also showed stronger antioxidant activity, and ultrasonic-assisted extraction could get high extraction rate of phenolic compounds.