To expand application of hawthorn (Crataegus pinnatifida Bge) fruit, the antioxidant and anti-lipidemic effects of haw pectin penta-oligogalacturonide (HPPS) prepared from hawthorn fruit were investigated in vitro and in mice. HPPS exhibited concentration-dependent scavenging activities against superoxide anion, hydroxyl and DPPH radicals. Additionally, HPPS supplementation significantly enhanced the antioxidant enzyme activities of superoxide dismutase, catalase, glutathione peroxidase, increased the total antioxidant capacity and the levels of glutathione, but lowered the malondialdehyde content in the liver of high-fat fed mice. Furthermore, HPPS significantly decreased the TG levels, the activity and the mRNA and protein levels of glycerol 3-phosphate acyltransferase (GPAT) and phosphatidate phosphohydrolase (PAP) in mice livers. Moreover, liver steatosis of mice associated with diffuse hepatocyte ballooning induced by a high-fat diet was markedly improved by a dose of 300 mg/kg HPPS-consumption. The results revealed that HPPS might be applicable as a dietary supplement for the prevention of fatty liver and oxidative damage.