This study aims to determine the inhibition of natural compounds P. crocatum against AChE enzyme activity. Inhibition of natural compounds of P. crocatum was analyzed by combining virtual screening and molecular docking methods with two different software, namely Autodock Tools 1.5.6 and YASARA Structure. This method is expected to improve the ability to identify potential natural compounds contained in betel leaf as AD drug candidates with AChE inhibition mechanism. A total of 21 natural compounds from three red betel leaf extract fractions (water fraction, ethyl acetate, and n-hexane) were analyzed for their binding affinity energy to AChE by virtual screening along with 664 active compounds known to have AChE inhibitory activity based on the DUD-E database to identify the potential of natural compounds for each fraction of red betel leaf (P. crocatum) inhibits AChE activity