Dietary phenolics exhibit hypolipidemic activity by changing lipid metabolism-related microRNA (miRNA) expression. Quercetin 3-O-rutinoside-7-O-α-l-rhamnosidase (quercetin 3-rut-7-rha), rutin and (-)-epicatechin are the main phenolics in lychee (Litchi chinensis Sonn.) pulp. A previous study reported that quercetin 3-rut-7-rha and rutin had hypolipidemic effects. To elucidate these effects and the underlying molecular mechanisms of lychee pulp phenolics (LPPs), the hepatic mRNA and protein expression of lipid metabolism-related genes and their associated miRNAs were measured after ten weeks of treatment with a high-fat diet (HFD) alone or in combination with LPPs. The administration of LPPs significantly reduced the HFD-induced increase in serum total cholesterol and triglyceride levels but increased the HDL-c content. The mRNA and protein expression levels of hepatic adenosine triphosphate-binding cassette transporter A1 (ABCA1) and carnitine palmitoyltransferase 1a (CPT1a) were upregulated, while fatty acid synthase (FAS) mRNA and the corresponding protein expression levels were downregulated by LPPs. Furthermore, the expression levels of miR-33, which directly modulates ABCA1 and CPT1a, and miR-122, which indirectly regulates FAS, were downregulated in mouse hepatocytes. The repression of miR-33 and miR-122 is a possible molecular mechanism of the hypolipidemic effects of LPPs in the liver. Our results suggest a novel hypolipidemic mechanism of LPPs.