OBJECTIVE: To analyze atherosclerosis progression and evaluate the histopathological changes in blood vessels in relation to the alterations in pancreatic b cell mass after feeding rats with only high-fat/sucrose (HFS) diet or in combination with phytochemical antioxidant compounds. STUDY DESIGN: Rats were fed on an HFS diet for 6 weeks and then were divided into 4 groups. The first group (HFS) was left untreated, and the other 3 groups were supplemented with quercetin (QU) (50 mg/kg), o-coumaric acid (CA) (75 mg/kg), or berberine (BB) (50 mg/kg). RESULTS: HFS-fed rats showed hyperglycemia, hyperinsulinemia, and dyslipidemia and alterations in the metabolic enzyme activities in serum and adipose tissue. The above observations were associated with foam cell formation in the subendothelial layer, and monocyte adhesion, and smooth muscle emigration, and calcium deposition on the degenerated intimal and medial layers of the aorta. The co-treatment with the phytochemical compounds QU, CA, and BB resulted in normoglycemic and hypolipidemic actions and modulation of metabolic and oxidative stress markers. CONCLUSION: Although each of these compounds reduced the progression of atherosclerosis initiated after feeding rats with an HFS diet, the BB seems to be most effective. Our analysis revealed a direct correlation between the histopathological alterations in the aorta wall of HFS-fed rats and other treated groups, and hence the progression of atherosclerosis signs were found to be correlated with β cell mass and the biochemical changes in these groups. © Science Printers and Publishers, Inc.