Flavonoids　are　potential　strikingly　natural　compounds　with　antioxidant　activity　and　acetylcholinesterase　(AChE)　inhibitory　activity　for　treating　Alzheimer＇s　disease　(AD).　In　present　study,　in　line　with　our　interests　in　flavonoid　derivatives　as　AChE　inhibitors,　a　four-dimensional　quantitative　structure-activity　relationship　(4D-QSAR)　molecular　model　was　proposed.　The　data　required　to　perform　4D-QSAR　analysis　includes　52　compounds　reported　in　the　literature,　usually　analogs,　and　their　measured　biological　activities　in　a　common　assay.　The　model　was　generated　by　a　complete　set　of　4D-QSAR　program　which　was　written　by　our　group.　The　best　model　was　found　after　trying　multiple　experiments.　It　had　a　good　predictive　ability　with　the　cross-validation　correlation　coefficient　Q(2)　=0.77,　the　internal　validation　correlation　coefficient　R-2　=0.954,　and　the　external　validation　correlation　coefficient　R-pred(2)　=　0.715.　The　molecular　docking　analysis　was　also　carried　out　to　understand　exceedingly　the　interactions　between　flavonoids　and　the　AChE　targets,　which　was　in　good　agreement　with　the　4D-QSAR　model.　Based　on　the　information　provided　by　the　4D-QSAR　model　and　molecular　docking　analysis,　the　idea　for　optimizing　the　structures　of　flavonoids　as　AChE　inhibitors　was　put　forward　which　maybe　provide　theoretical　guidance　for　the　research　and　development　of　new　AChE　inhibitors.