Abstract Natural products inhibiting fatty acid synthase (FAS) are appearing as potential therapeutic agents to treat cancer and obesity. The bioassay-guided chemical investigation of the hulls of Nephelium lappaceum L. resulted in the isolation of ten compounds ( 1– 10) mainly including flavonoids and oleane-type triterpene oligoglycosides, in which all of the compounds were isolated from this plant for the first time. Additionally, compounds 8 and 9 were new hederagenin derivatives and were elucidated as hederagenin 3- O-(2,3-di- O-acetyl-α- l-arabinofuranosyl)-(1→3)-[α- l-rhamnopyranosyl(1→2)]-β- l-arabinopyranoside and hederagenin 3- O-(3- O-acetyl-α- l-arabinofuranosyl)-(1→3)-[α- l-rhamnopyranosyl-(1→2)]-β- l-arabinopyranoside, respectively. All these isolates were evaluated for inhibitory activities of FAS, which showed these isolates had inhibitory activity against FAS with IC 50 values ranging from 6.69 to 204.40 μM, comparable to the known FAS inhibitor EGCG (IC 50 = 51.97 μM). The study indicates that the hulls of Nephelium lappaceum L. could be considered as potential sources of promising FAS inhibitors and the oleane-type triterpene oligoglycosides could be considered as another type of natural FAS inhibitors.