Pectin, a natural polysaccharide found in the cell wall of most higher plant such as citrus, has drawn much attention due to its potential beneficial role in facilitating the treatment of many diseases like cancer, hyper cholesterol and diabetes. However, the broad application of pectin faces great limitations as the large molecular size of pectin severely prevents its bioavailability in vivo. In this study, we report an effective and highly convenient approach to degrade natural pectin into lower molecular pectin. By combining ultrasound with Fenton system (US-Fenton), we show that ultrasound synergistically enhances the efficiency of Fenton reaction to degrade pectin into 5.5 kDa within only 35 minutes. Importantly, RG-I domain, the most effective portion of natural pectin, was well preserved and highly enriched. In addition, the antioxidant activities of US-Fenton-treated pectin was significantly elevated. The mechanism of this novel observation was further investigated through the multiple structural analyses including HPLC, IR and NMR. Taken together, we present a novel and convenient approach to generate ultra-low molecular weight pectin with high efficiency and higher bioactivity. We expect our approach will have broader applications in improving the bioavailability and bioactivity of other polysaccharide-based natural compounds.