10-Dehydrogingerdione is a novel cholesteryl ester transfer protein (CETP) inhibitor of natural origin. Some synthetic CETP inhibitors have recently been reported to suppress proprotein convertase subtilisin/kexin type 9 (PCSK9). Therefore, the present study aimed mainly to clarify the effect of 10-Dehydrogingerdione on cellular adhesion inflammatory molecules, platelet activation and endothelial dysfunction markers in addition to PCSK9 as compared to atorvastatin in dyslipidemic rabbits. Dyslipidemia was induced in 30 male rabbits, distributed in 3 equal groups through feeding dietary cholesterol (0.5% w/w) for 3 months. Two dyslipidemic groups were concurrently treated with either atorvastatin or 10-Dehydrogingerdione (10 mg/kg/ day, p.o) and dietary cholesterol. One additional group including 10 normal rabbits fed normal diet served as normal control (NC) group. Both 10-Dehydrogingerdione and atorvastatin significantly reduced serum CETP level and activity as well as PCSK9 and low density lipoprotein cholesterol (LDL-C) levels but increased high density lipoprotein cholesterol (HDL-C) levels as compared to dyslipidemic control (DC) rabbits (p <  0.001). Both treatments also induced a marked decrease in the interferon-gamma (IFN-γ), soluble CD40 ligand (sCD40L) and soluble P-selectin (sP-selectin) levels, inflammatory cell infiltration, as well as atherogenic and coronary risk indexes in addition to aortic atheromatous changes and intima/media ratio, respectively as compared to the DC group (p <  0.001). The reduction in these markers showed a significant correlation with PCSK9 suppression and CETP inhibitory effect. Interestingly, 10-Dehydrogingerdione exerted a greater ameliorative potential regarding these biomarkers than atorvastatin. Our findings suggest that 10-Dehydrogingerdione is a promising PCSK9 inhibitor with a significant protective value against many atherosclerotic risk factors.