High-fat diet (HFD) can cause hyperlipidemia, fatty liver and cardiovascular disorders. Herein, we evaluated therapeutic effects and possible underlying mechanisms of actions of Schistosoma mansoni soluble egg antigen (SEA) against experimental HFD induced dyslipidemia, hepatic and cardiovascular pathology. Forty Swiss albino mice were divided into four groups (10 each); mice fed standard diet (SD), mice fed HFD, mice fed HFD for 8 weeks then infected by S. mansoni cercaria (HFD+I) and mice fed HFD for 8 weeks then treated with SEA (HFD+SEA), all mice were euthanized 16 weeks after starting the experiment. HFD+SEA mice showed significantly (p<0.001) reduced total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG), and significantly (p<0.05) increased high-density lipoprotein cholesterol (HDL-C) comparing to HFD mice with non-significant difference with HFD+I mice group. Doppler flowmetry showed significantly (p<0.01) lower arterial resistance and significantly (p<0.05) higher blood flow velocity in HFD+SEA and HFD+I mice groups than HFD mice. HFD+SEA mice revealed improving in liver and aortic pathology and these were better than HFD+I mice group. HFD+SEA and HFD+I mice groups had less myocardium lipid deposits, but still showing some congested blood vessels. HFD myocardium revealed strong CD34+ expression on immunohistochemistry study, while that of HFD+SEA showed weak and HFD+I mice had moderate expressions. HFD+SEA mice had significantly (p<0.01) lower serum IL-1β and vascular endothelial growth factor (VEGF) and significantly (p<0.001) higher serum transforming growth factor beta 1 (TGF-β1) and IL-10 than HFD mice with non-significant difference with HFD+I mice. In conclusion, SEA lowered serum lipids, improved aortic function, decreased liver and cardiovascular pathology in HFD mice, so, it is recommended to purify active molecules from SEA to develop anti-dyslipidemic treatment.