A naturally occurring xanthone, mangostanin (1,3,6-trihydroxy-7-methoxy-2,8-bis(3-methylbut-2-en-1-yl)-9 H-xanthen-9-one), was isolated from Garcinia mangostana L. It demonstrates a range of pharmacological effects, such as antibacterial, antifungal, antiviral, anti-inflammatory, and anticancer activity. The α-mangostin’s isoprenyl and benzopyrone skeleton side chains are crucial to its antibacterial activity. In this review, we review the current approach for the isolation of α-mangostin from plant sources and the recent report on its biological activity. The structure–activity relationship is discussed to demonstrate the pharmacophore of α-mangostin responsible for its anti-infective properties, including antibacterial, antifungal, and antiviral activities. The potential approaches for developing α-mangostin for the treatment of infectious diseases are proposed as future perspectives.