Andrographis paniculata (A. paniculata) is a medicinal plant traditionally used as anti-inflammation and anti-bacteria herb. Andrographolide, the major active component of A. paniculata, exhibits diverse pharmacological activities, including anti-inflammation, anti-cancer, anti-obesity, anti-diabetes, and other activities. In this article, we comprehensively review the therapeutic potential of A. paniculata and andrographolide focusing on the mechanisms of action and clinical application. We systemically discuss the structure-activity relationship of andrographolide and derivatives. Despite the various pharmacological activities and formula of A. paniculata and andrographolide, we propose further development of more structural derivatives of andrographolide with reduced toxicity and increased therapeutic efficacy is still needed for the clinical application of this ancient mighty herb and its major component.