A set of 76 derivatives of the epimeric tricyclic sesquiterpenols longifolol and isolongifolol was subjected to inhibition and glucuronidation assays employing the human UDP-glucuronosyltransferase (UGT) 2B7. Detailed structure-activity relationships (SARs) with respect to functionality, stereochemical properties, and steric features were derived. To gain further insight into the SARs of UGT2B7 ligands herein, we have developed a 3D-quantitative structure-activity relationship (3D-QSAR) using Comparative Molecular Similarity Analysis (CoMSIA). The formation of the enzyme-inhibitor complex was predominantly controlled by spatially directed hydrophobic interactions. The glucuronidation rate was significantly influenced by the steric demand of substituents in proximity of the nucleophilic hydroxy group. The glucuronidation of the compounds was prevented by the introduction of bulky substituents such as isopropyl, tert-butyl, and phenyl groups. The epimeric longifolol derivatives of series D were the best inhibitors displaying IC(50) values as low as 4.6 nM. This study shows that high-potency substrates can be turned into potent inhibitors by addressing functional, stereochemical, and steric properties.