Hypercholesterolemia, cholesterol-enriched diet and oxidative stress have been shown to increase serum total cholesterol (TC) and low density lipoprotein-cholesterol (LDL-C) levels resulting in development of atherosclerosis. Antioxidants play an important role in inhibiting and scavenging free radicals, thus providing protection to humans against infectious and degenerative diseases. The present study was undertaken to examine the possible protective effects of propolis (a resinous hive product collected by honeybees from various plant sources) and thymoquinone (TQ, active constituent of Nigella. Sativa seeds oil) on serum lipid levels and early atherosclerotic lesions in hypercholestrolemic rabbits. New Zealand rabbits were fed on either standard chow or atherogenic diet during four weeks and concomitantly received either propolis or TQ. At the end of experiment period, serum samples were collected to determine lipid profile, kidney functions and antioxidant status. Tissues from aorta, pulmonary artery and kidney were taken for histopathological examination. The cholesterol-enriched diet induced a significant increase in serum TC, triglycerides, LDL-C, thiobarbituric acid-reactive substances concentrations and a significant decrease in high density lipoprotein-cholesterol and in reduced glutathione levels compared to control group. Administration of propolis or TQ with cholesterol-enriched diet significantly (p < 0.05) reduced TC, LDL-C, triglycerides and thiobarbituric acid-reactive substances concentrations, while increased high density lipoprotein-cholesterol concentration, as well as glutathione content compared to high cholesterol (HC) control group. Kidney function parameters were significantly affected by cholesterol diet and both propolis and TQ counterregulated the cholesterol-induced changes. Histopathologically, early athersclerotic changes were observed in HC control group represented by endothelial damage and thickened foam cells while propolis or TQ provided protection against the HC-induced damage. In conclusion, the present study suggests the potential beneficial effects of both propolis and TQ in diminishing the risk of atherosclerosis via antioxidant mechanism.