Our objective was to prepare some isatin derivatives. The compounds were purified using a silica gel column and identified by FT-IR and ¹HNMR. This study was designed to investigate the anti-atherosclerosis effect of the preparative Spiro isatin derivatives on lipid profile, cardiac markers, liver, and kidney function in atherosclerosis rats. The experiment was designed, and the total number of animals was 25 rats. We divided them into groups of 5 rats each, with a (negative) group receiving only distilled water and an (positive) group receiving cholesterol (500 mg/kg of body weight with coconut oil) orally to induce atherosclerosis for 25 days. The other groups received isatin compounds (0.571 mg/kg of body weight for 30 days) orally. Blood, cardiac, and aorta tissue samples were collected. The results indicated a significant decrease in the levels of MDA, cTnI, CK-MB, T.chol, T.G., LDL-c, and VLDL-c for all compounds prepared compared to the positive control. Compound C showed a significant decrease in the levels of urea and creatinine and a significant increase in their level of HDL-c compared to the control. Compound  B showed a significant decrease in the levels of AST, ALT, and myoglobin and a significant increase in levels of HDL-c and GSH compared to the control. The results also indicated that compound A significantly reduced the levels of ALT, myoglobin, and creatinine and showed a significant increase in levels of GSH compared to the control. In tissue sections, compound C showed positive effects on cardiomyocytes and the aorta compared to the healthy control group.