Abstract: This study aimed to evaluate the hypolipidemic efficacy and underlying mechanisms of Antarctic krill oil (KO) in combination with red yeast rice (RYR) and coenzyme Q10 (CoQ10). Hyperlipidemic rats models were established through high-fat and high-cholesterol diet feeding. After model being built, the rats received oral gavage of 200 mg/kg/d Antarctic krill oil, 15 mg/kg/d red yeast rice, 3.5 mg/kg/d coenzyme Q10, or their combinations for 4 weeks. The results showed that Antarctic krill oil, red yeast rice, coenzyme Q10, and their combined formulations significantly reduced serum levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), alanine aminotransferase (ALT), aspartate aminotransferase (AST), weight of visceral adipose tissue and hepatic lipid accumulation in hyperlipidemic rats (P<0.01), with the combined intervention groups exhibiting superior effects. The combination groups notably increased serum high-density lipoprotein cholesterol (HDL-C) levels (P<0.01). Mechanistic investigations revealed that all interventions reduced hepatic malondialdehyde (MDA), tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) levels, while elevating reduced glutathione (GSH) and superoxide dismutase (SOD) levels (P<0.05). The combined formulations showed superior effects compared to individual interventions. Compared to the model group, all interventions up-regulated the expression of adenosine monophosphate-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor α (PPARα) in liver tissue (P<0.01) and down-regulated the expression of sterol regulatory element-binding protein 1C (SREBP-1C) and peroxisome proliferator-activated receptor γ (PPARγ) (P<0.01). Additionally, all interventions significantly reduced serum bile acid levels (P<0.05), increased hepatic bile acid content (P<0.05), enhanced fecal excretion of bile acids, TC, and TG (P<0.05), and elevated fecal concentrations of short-chain fatty acids concentrations (P<0.05). In summary, krill oil, red yeast rice, and coenzyme Q10 could effectively improve hyperlipemia, with their combined formulations showed more optimal effects. The potential mechanisms involved improving hepatic lipid metabolism, alleviating hepatic oxidative stress and chronic inflammation, regulating bile acids metabolism, increasing fecal lipids excretion, and elevating fecal short-chain fatty acids levels. This study provides theoretical support and references for the development of hypolipidemic functional foods and health products and offers new insights into the development of the krill oil industry.