Green propolis produced by Apis melífera bees, having Baccharis dracunculifolia D.C. (Asteraceae) as the primary botanical source, has been used in traditional medicine to treat numerous disorders. However, studies evaluating propolis' potential in treating cardiovascular diseases via its effects on cholesterol metabolism are lacking. Therefore, this study investigated the effects of green propolis extracts on lipid metabolism in hypercholesterolemic guinea pigs. Chemical characterization of ethanolic extracts of green propolis samples was undertaken using HPLC. The in vitro characterization included an evaluation of the antioxidant capacity of the hydroalcoholic extract of green propolis (DPPH and FRAP assays) and its ability to act as an inhibitor of the HMG-CoA reductase enzyme. In vivo, we investigated the effect of the hydroalcoholic extract of green propolis on lipid metabolism in hypercholesterolemic guinea pigs. Results obtained validated previous reports of significant antioxidant activity. HPLC analysis confirmed that coumaric acid, artepillin C, and baccharin were the most common and abundant compounds in green propolis samples among the studied compounds. Furthermore, the compounds in these extracts acted as effective HMG-CoA reductase inhibitors in vitro. In vivo assays demonstrated that a hypercholesterolemic diet significantly reduced serum levels of the HDL cholesterol fraction. Simvastatin and propolis hydroalcoholic extracts promoted a significant increase in HDL cholesterol, suggesting that these extracts can improve the serum lipid profile of hypercholesterolemic guinea pigs. Results obtained in this study provide a perspective on the possible hypocholesterolemic effect of green propolis, suggesting that it can improve the serum lipid profile in hypercholesterolemic guinea pigs.