Atherosclerosis, a chronic inflammatory disease of the arterial wall, is a leading cause of cardiovascular morbidity and mortality. Current pharmacotherapies may exhibit limitations in efficacy and tolerability, prompting interest in multi-target natural interventions. M3PV is a novel polyherbal, micronutrient-based formulation specifically designed to exert anti-atherogenic effects through complementary lipid-lowering, anti-inflammatory and antioxidant mechanisms. Our study evaluated the anti-atherogenic potential of M3PV in a rabbit model of diet-induced atherosclerosis. A total of 35 male New Zealand White rabbits were randomised into five groups, fed a high-cholesterol diet and treated with M3PV (216 or 648 milligrams per kilogram of body weight per day (mg/kg b.w./day)) or atorvastatin (2.4 mg/kg b.w./day) as a reference drug in this 10-week study conducted at Hanoi Medical University. Lipid profiles, liver function enzymes, oxidative stress markers and inflammatory biomarkers were assessed. Aortic and hepatic tissues were analysed macroscopically and microscopically. M3PV mg/kg b.w./day at 216 mg/kg b.w/day significantly improved serum levels of total cholesterol, triglycerides, low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) (p < 0.05), with no statistical difference compared with the atorvastatin-treated group. M3PV reduced oxidative stress and inflammation by significantly decreasing lactate dehydrogenase (LDH) and malondialdehyde (MDA) (p < 0.01) and increasing superoxide dismutase (SOD), reduced glutathione (GSH) and nitric oxide synthase (NOS) (p < 0.001). Histological analysis showed substantial reductions in aortic lesion area (reduced from 60.11 ± 19.84 % in the model group to 18.23 ± 9.72 % and 20.34 ± 10.25 % for the 216 and 648 mg/kg dose groups, respectively; p < 0.01) and hepatic tissue injury scores compared with the untreated group. M3PV at 648 mg/kg b.w/day exerted effects similar to the lower dose initially but were less sustained over the 10-week period, while demonstrating potent antioxidative activity. M3PV exhibits significant anti-atherogenic and hepatoprotective effects in a rabbit model of diet-induced atherosclerosis, likely attributable to lipid-modulating, antioxidative and anti-inflammatory mechanisms. These findings support M3PV as a promising natural therapeutic candidate for the management of atherosclerosis.