Cape gooseberry, the berry of Physalis pubescens L., is very popular as a folk medicine and a fruit in the northeast of China. Bioassay-guided fractionation of this delicious fruit led to the isolation and identification of 15 compounds from the 60 and 30% EtOH fractions that exhibited potent antioxidant activities. Among these isolated compounds, calceolarioside A (7), quercetin-3-O-β-d-glucopyranoside (11), caffeic acid (12) and 1-O-caffeoyl-β-d-glucopyranoside (13) showed higher antioxidant activity, with EC50 values in the range of 0.51–1.86 μM, when compared to the positive control vitamin E, with an EC50 value of 3.61 μM. These results suggested that flavonoids and caffeic acid derivatives as major compounds in Cape gooseberry might play an important role in contributing to the health benefits of this fruit. Practical Applications Cape gooseberry, the berry of Physalis pubescens L., is one of the commercial fruits of particular interest to the world's up-scale food industry. This plant could provide significant health benefits because of their high antioxidant, vitamin, mineral and fiber contents.