Hericium erinaceus polypeptide (HEP) was prepared by an ultrasound-microwave assisted enzymatic method. Using an ultrafiltration membrane with molecular weights of 5 and 10 kDa, HEP was fractionated into three fractions, namely, (HEP-I (< 5 kDa), HEP-II (5–10 kDa), and HEP-III (> 10 kDa)). In vitro chemical methods were used to compare the antioxidant and hypolipidemic abilities of the polypeptide fractions from H. erinaceus before and after simulated gastrointestinal digestion. By constructing a hyperlipidemia model, the hypolipidemic ability of the high active fraction (HEP-II) was verified. The results showed that the antioxidant and hypolipidemic abilities of the polypeptide fractions from H. erinaceus did not change dramatically during simulated gastrointestinal digestion in vitro. The polypeptide fractions from H. erinaceus exhibited high tolerance to simulated gastrointestinal digestion in vitro, with strong antioxidant and hypolipidemic activities. HEP-II with a molecular weight of 5–10 kDa had the best stability, antioxidant, and hypolipidemic abilities in gastrointestinal digestion. The secondary structure of HEP-II was mainly composed of random coil (18.36%) and α-helix (47.71%) structures, which was beneficial to the hypolipidemic ability of HEPII. Animal experiments showed that compared to the high-fat model group, HEP-II could inhibit the weight gain of the mice, decrease the liver index and serum levels of the serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), nitric oxide synthase (NOS), alanine aminotransferase (AST), and glutamic-pyruvic transaminase (ALT), increase the levels of glutathione peroxidase (GSH-Px) and high-density lipoprotein cholesterol (HDL-C), decrease the arteriosclerosis index (AI), and improve the hemorheological indices of the mice. In addition, the whole blood and plasma viscosities of the mice decreased, and HEP-II increased the level of superoxide dismutase (SOD) in the liver, reducing the level of malondialdehyde (MDA), and the degree of oxidative stress in the liver of hypolipidemia mice. Furthermore, HEP-II improved liver steatosis. These results indicated that the polypeptide fractions from H. erinaceus all had a potential hypolipidemic effect, and HEP-II had the strongest potential hypolipidemic effect.