Atherosclerosis (AS) is a major cause of cardiovascular diseases (CVDs) and a strong link with hepatic steatosis. Silver carp muscle hydrolysate (SCH) possess various beneficial activities but its effect on AS and hepatic steatosis is yet unknown. This study aimed to investigate the effects of SCH on AS lesions and hepatic steatosis using apoE-/- mice. Results showed that SCH significantly reduced the vascular AS plaques and alleviated hepatic steatosis lesions in apoE-/- mice. Consistent with this, the lipid levels both in circulation and liver were lowered by SCH. The mechanism analysis showed SCH down-regulated the expression of genes involved in lipoproteins production while up-regulated the expression of genes related to reverse cholesterol transport (RCT) in liver. Meanwhile, SCH remarkably promoted transintestinal cholesterol excretion (TICE) process in intestine, partly contributing to the reduction of blood lipids. The peptide profile data indicated LYF, HWPW, FPK, and YPR are the main peptides in SCH that play a vital role in alleviating AS lesions and hepatic steatosis. Our findings provided new knowledge for the application of SCH in ameliorating CVDs and liver diseases.