Here, we present a series of novel paeonol derivatives that prevent lipid accumulation at lower doses and exhibit improved water solubility. According to SAR analysis results, 1-(4-methoxy-2-(2-(piperidin-1-yl)ethoxy)phenyl)ethanone (6a) and 4′-methoxy-2′-[(phenylsulfonyl)oxy]acetophenone (7a) demonstrate as good inhibition ability at low-dose (10 μg mL⁻¹) as that of paeonol at high-dose (100 μg mL⁻¹). In addition, compounds 6a and 7a can be synthesized quantitatively with simple preparation methods. Hence, we believe that compounds 6a and 7a are potentially suitable antiatherogenic compounds for future drug development.