Policosanol (POL) is a hypocholesterolemic drug of natural origin and has been shown to reduce circulating levels of proprotein convertase subtilisin/kexin type 9 (PCSK9) in healthy participants. Recently, we have reported that POL can attenuate aortic calcification in diabetic dyslipidemic rats; however, the underlying mechanism is not fully elucidated. We aimed to investigate the effect of POL on aortic calcification and whether PCSK9 has a contributory role and also to examine whether the combination of POL with pentoxifylline (PTX) as anti-tumor necrosis factor α would offer additional benefits. Thirty adult male New Zealand rabbits weighing 1.5 to 2 kg were randomly assigned to 5 groups. One group received standard chow diet and served as normal control group (NC). The other 4 groups received 0.5% wt/wt cholesterol-rich diet for 12 weeks and concurrently treated with placebo, POL, PTX, or a combination of POL and PTX. Sera samples and aortic tissue were collected for biochemical measurements and histological assessment. Rabbits fed a cholesterol-rich diet demonstrated dyslipidemia, increased inflammatory state, and elevated serum levels of PCSK9, compared to the NC group. Aortic calcification was evident in dyslipidemic rabbits, represented by increased calcium deposition and osteopontin expression in aortic tissue, along with elevated serum levels of alkaline phosphatase and osteocalcin. Dyslipidemic rabbits showed a significant upregulation of wingless-type MMTV integration site family 3A and bone morphogenetic protein 2 genes in their aortic tissue. Policosanol significantly reduced circulating PCSK9 levels, suppressed calcification markers, and attenuated aortic calcification. Combination of POL with PTX alleviated aortic calcification to a greater extent than either monotherapy, which may be attributed to further suppression of PCSK9 and calcification markers. These findings suggested that POL exerted anticalcifying effect partly via inhibition of PCSK9. Combination of POL and PTX offered additional benefits and might represent a promising therapeutic option for aortic calcification.