Acetylcholinesterase (AChE) is an importantenzyme in the pathogenesis of Alzheimer’s disease (AD). Comparative quantitative structure-activity relationship(QSAR) analyses on some huprines inhibitors againstAChE were carried out using comparative molecular fieldanalysis (CoMFA), comparative molecular similarityindices analysis (CoMSIA), and hologram QSAR(HQSAR) methods. Three highly predictive QSAR modelswere constructed successfully based on the training set. The CoMFA, CoMSIA, and HQSAR models have valuesof r2 = 0.988, q2 = 0.757, ONC = 6; r2 = 0.966, q2 =0.645, ONC = 5; and r2 = 0.957, q2 = 0.736, ONC = 6. The predictabilities were validated using an external testsets, and the predictive r2 values obtained by the threemodels were 0.984, 0.973, and 0.783, respectively. Theanalysis was performed by combining the CoMFA andCoMSIA field distributions with the active sites of theAChE to further understand the vital interactions betweenhuprines and the protease. On the basis of the QSAR study,14 new potent molecules have been designed and six ofthem are predicted to be more active than the best activecompound 24 described in the literature. The final QSARmodels could be helpful in design and development ofnovel active AChE inhibitors.