In this work, we investigated the inhibitory activities of aqueous extract (Eaq), 30, 60, and 95 % ethanol extracts (E3et, E6et, and E9et), petroleum ether extract (Epe), ethyl acetate extract (Eae), and 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone (DMC) from Cleistocalyx operculatus flower buds on pancreatic lipase and α-amylase, which were closely related to body weight and obesity. The inhibition effect of various extracts was determined by the Lineweaver–Burk plots. The results showed that the IC50 values of DMC, Epe, Eae, and E9et against pancreatic lipase were 101.5 μM, 38.65, 76.62, and 109.76 μg/ml, respectively, which were much lower than that of E3et and E6et. Eaq, E3et, E6et, and DMC strongly inhibiting the pancreatic α-amylase, with IC50 values of 73.10, 165.93, 231.23 μg/ml, and 69.35 μM, respectively. Furthermore, the kinetic analysis suggested that the inhibition mode of crude extract against pancreatic lipase was noncompetitive, while that against pancreatic α-amylase was competitive. The content of DMC and total polyphenols in each extract were determined by HPLC and spectrophotometric method, respectively. It was interestingly found that the DMC content had profound influence on pancreatic lipase activity, and the total polyphenols content significantly affected the pancreatic α-amylase activity. The findings in this work suggested that extracts from C. operculatus flower buds possess potent inhibitory activity against pancreatic lipase and α-amylase, and provided some new ideas for the prevention and treatment for obesity.