Background Atherosclerosis (AS) is a chronic condition in which dyslipidemia had been contributed to its development, along with evidence proving an inflammatory cause. Objective The aim was to determine the relation between dietary hypercholesterolemia and AS with a trial to evaluate the role of inflammation in development of AS in male albino rats. Materials and methods A total of 30 adult male albino rats were divided into two main groups: control group (n=6) and high-cholesterol diet (HCD)-fed group (n=24), which was subdivided into four subgroups (n=6): HCD-fed, HCD-fed with methotrexate, HCD-fed with cholestyramine, and HCD-fed with statin groups. Serum total cholesterol (TC), triglycerides, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, lowdensity lipoprotein (LDL)-cholesterol, very LDL-cholesterol, atherogenic index, LDL/HDL ratio, and inflammatory markers such as inerlukin-6, tumor necrotic factor-α, and highly sensitive C-reactive protein were estimated. Carotid artery histopathology was done. Results HCD produced marked disturbance in lipid profile and increased inflammatory markers and atherosclerotic changes in carotid artery. Administration of statin and cholestyramine significantly improved this dyslipidemia. Elevated inflammatory markers were significantly decreased by administration of methotrexate and statin. Atherosclerotic changes in carotid artery decreased significantly in rats pretreated with methotrexate and statin. Conclusion Atherosclerotic condition is closely associated with excessive intake of cholesterolrich diet; however, inflammation has a central role in the pathogenesis of the atherosclerotic process, as atherosclerotic changes could be reduced despite disturbed lipid profile by anti-inflammatory medication. Further studies are recommended for more evaluation of the role of anti-inflammatory drugs in reduction of clinical outcomes in atherosclerotic conditions.