Syringin is a phenylpropanoid glycoside isolated from the bark of Syringa vulgaris. Phillygenin is a lignan obtained mainly from the fruits and flowers of Forsythia intermedia. Both compounds have shown potent anti-inflammatory and antioxidant properties. We investigated the potential role of syringin and phillygenin in preventing lipid deposition in macrophages. Syringin and phillygenin significantly (p < 0.001) reduced lipid deposition in macrophages in a dose-dependent manner. For syringin, the greatest reduction in CD36 receptor expression was found to be over 80% (50 μg/mL) compared to the cholesterol-stimulated control (p < 0.001). Phillygenin inhibited CD36 receptor expression by approximately 25% (50 μg/mL), compared to the stimulated control (p < 0.05). For syringin, the CD36 receptor regulation pathway was PPAR-γ dependent. Phillygenin showed a statistically significant (p < 0.001) increase in the expression of the ABCA1 transporter: 2.5-fold (10 μg/mL), 3-fold (20 μg/mL) and 4-fold (50 μg/mL) compared to the cholesterol-stimulated control. Syringin did not significantly increase ABCA1 expression. For phillygenin, the activation pathway of the ABCA1 transporter was HO-1dependent. Our study showed that syringin inhibits the cholesterol-induced differentiation of macrophages into foam cells. Moreover, phillygenin increased cholesterol efflux from macrophages. Therefore, syringin and phillygenin may be valuable agents in the prevention of early and late atherosclerosis.