Abstract Our study aimed to illustrate the effect of the antihistaminic drug azelastine on aortic calcification in diabetic hyperlipidemic (DH) rats along with the underlying molecular mechanism. Twenty-four male albino Wistar rats were categorised into four groups. One group received normal rodent chow (normal group), while the other groups were rendered diabetic and hyperlipidemic; one received no drugs and served as a positive control while the other two groups received either azelastine (4 mg/kg) or 10-dehydrogingerdione (10 mg/kg) orally and daily for 8 weeks. Azelastine significantly reduced blood glucose, HbA1c and serum ALP, OCN, downregulated apo B, improved the lipid profile (LDL-c decrease and HDL-c increase), attenuated calcium deposition and aortic calcification as compared to control group. 10-DHGD showed comparatively lower effect. Anti-calcifying effect of azelastine might be related to upregulation of apo A (HDL-c) and downregulation of apo B mRNA expression indeed good modulator of aortic calcification.: Many studies have indicated that high-density lipoprotein-cholesterol (HDL-c) is inversely correlated with atherosclerotic plaque progression and could reduce cardiovascular disease risk. An anti-calcifying effect of HDL-c has been reported and targeting this lipoprotein may therefore be a valuable approach to vascular calcification control. Azelastine is a selective H1 antagonist that was identified to increase mRNA expression of apolipoprotein A. This encouraged us to investigate the effect of azelastine on lipid profile and markers of aortic calcification in DH rats. Our findings showed that azelastine ameliorated aortic calcification and increased apoA expression along with a decline in apo B. This may represent the underlying mechanism while the histopathological findings offered a significant support to the collected biochemical data.