DescriptionAnnona muricata is a perennial tree found in most tropical areas of the world, including Western Africa, Central and South America and Southeast Asia. It has been used around the world medicinally by several cultures. Some of these cultures use A. muricata as an anxiolytic tea given to unruly patients. Traditional anxiolytic uses of Annona muricata in medicine have long existed, without knowledge of the active compound or compounds. We aim to scientifically support and extend these traditional uses by characterizing the bioactive compound(s) within the leaf extract. The active structures can then be modified to provide potentially new classes of active drugs. The anti-anxiety effects of A. muricata seen in traditional medicine were characterized by using a set of widely-accepted behavioral models of anxiolytic effects in mice. Partial phytochemical profiling done through ultra-high performance liquid chromatography (UHPLC) and gas chromatography-mass spectrometry (GC-MS) has identified a list of compounds that comprise the different fractions of the leaf extract. Through the mouse behavioral investigations, an active fraction has been determined to have a sedative effect, and through a dose-response study, an anxiolytic-like activity has been determined for the same fraction. Further fractionation of the extract and subsequent mouse behavioral studies have resulted in the discovery of smaller groups of potentially active compounds that can be fully profiled and modeled using Computer-Aided Drug Discovery (CADD). The use of mouse behavioral models of anxiolytic effects and the chromatographic analysis of the leaf extract allowed the identification of active fractions in aqueous extract. Both sedative and anxiolytic-like concentrations of the extract’s polar components were demonstrated, and further profiled. The profiled chemical compounds can be modeled to better suggest which compounds may provide the bioactive effects in vivo.