This study aimed to elucidate the therapeutic potential and underlying mechanisms of the Citri Reticulatae Pericarpium extract(CRPE) against hypercholesterolemia. A hypercholesterolemic rat model was established through a combination of a high-sugar, high-fat diet and ethanol administration. The experimental animals were systematically divided into several groups, including a normal control group, a disease model group, a positive control group treated with ezetimibe(1 mg·kg~(-1)), and three intervention groups receiving low, medium, and high doses of CRPE(1.25, 2.5, and 5 g·kg~(-1), respectively). High performance liquid chromatography(HPLC) revealed that CRPE mainly contained narirutin, hesperidin, and nobiletin. A comprehensive series of in vivo assessments were conducted to evaluate effects of the extract. These included measuring serum lipid levels and calculating the atherogenic index(AI) using an automated biochemical analyzer, quantifying total cholesterol(TC) and total bile acid(TBA) levels in liver tissues and fecal samples with commercial assay kits, evaluating microcirculatory blood perfusion in the tail using the Moor FLPI laser speckle contrast imaging system, and measuring hemorheological parameters with an automated hemorheometer. Furthermore, enzyme-linked immunosorbent assay(ELISA) was employed to measure the serum and hepatic levels of critical factors involved in cholesterol transport and metabolism. The expression of proteins related to the reverse cholesterol transport(RCT) pathway and bile acid synthesis and metabolism in the liver was meticulously examined by Western blot. In vitro cell experiments were performed to validate the effects of CRPE on cholesterol uptake and efflux in BRL and RAW264.7 cells. The findings demonstrated that CRPE effectively corrected dyslipidemia, enhanced microcirculatory perfusion, and ameliorated abnormal blood rheology. It reduced serum levels of oxidized low-density lipoprotein(ox-LDL), apolipoprotein B(ApoB), free cholesterol(FC), cholesteryl ester(CE), and acyl coenzyme A: cholesterol acyltransferase(ACAT), while simultaneously increasing the levels of lecithin: cholesterol acyltransferase(LCAT) and apolipoprotein A1(ApoA1). A notable reduction in hepatic TC and a significant increase in TBA content in both the liver and feces were observed. Mechanistically, the hypocholesterolemic effect of CRPE was attributed to its ability to upregulate the expression of pivotal proteins in the RCT pathway, including the low-density lipoprotein receptor(LDL-R), scavenger receptor class B type I(SR-BI), ATP-binding cassette sub-family G member 5(ABCG5), ATP-binding cassette sub-family G member 8(ABCG8), and ATP-binding cassette subfamily B member 1(ABCB1). Concurrently, CRPE modulated the expression of central regulators of bile acid homeostasis, such as the bile salt export pump(BSEP), the farnesoid X receptor(FXR), and cholesterol 7α-hydroxylase(CYP7A1). The in vitro experiments provided compelling corroborating evidence, showing that CRPE directly stimulated the uptake of NBD-cholesterol in BRL hepatocytes and promoted its efflux from RAW264.7 macrophages. In conclusion, CRPE ameliorates hypercholesterolemia by facilitating RCT and maintaining enterohepatic circulation homeostasis of bile acid.